curcumin and Mouth-Neoplasms

Oral cancer (OC) is the eighth most common cancer, particularly prevalent in developing countries. Current treatment includes a multidisciplinary approach, involving chemo, radio, and immunotherapy and surgery, which depends on cancer stage and location. As a result of the side effects of currently available drugs, there has been an increasing interest in the search for naturally-occurring bioactives for treating all types of cancer, including OC. Thus, this comprehensive review aims to give a holistic view on OC incidence and impact, while highlights the preclinical and clinical studies related to the use of medicinal plants for OC prevention and the recent developments in bioactive synthetic analogs towards OC management. Chemoprophylactic therapies connect the use of natural and/or synthetic molecules to suppress, inhibit or revert the transformation of oral epithelial dysplasia (DOK) into oral squamous cell carcinoma (OSCC). Novel searches have underlined the promising role of plant extracts and phytochemical compounds, such as curcumin, green tea extract, resveratrol, isothiocyanates, lycopene or genistein against this malignancy. However, poor bioavailability and lack of

Topics: Carcinoma, Squamous Cell; Curcumin; Genistein; Humans; Isothiocyanates; Lycopene; Mouth Neoplasms; Phytochemicals; Plant Extracts; Resveratrol; Tea

Oral squamous cell carcinoma (OSCC) is a growing global public health problem for which standard therapeutic strategies have failed to contribute significantly to improve the survival rates that have remained around 50% over the past three decades. Therefore, there is a pressing need for new therapeutic strategies. Curcumin is a natural dietary compound with known anti-neoplastic activities, hence its classification as a nutraceutical agent. This review presents the current in vitro and in vivo studies in which curcumin has been examined for its anti-cancer potential in treating OSCC. Its mechanisms of action are also beginning to become unveiled. The available studies have been focusing on the impact of curcumin on epithelial malignant cells, but overlooking the components of the tumor microenvironment. Curcumin has been emerging as a promising therapeutic agent in oral cancer, either alone or in combination with standard therapeutic agents, and will probably become of practical use once its route of administration has overcome its poor bioavailability.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Curcumin; Dietary Supplements; Epithelial Cells; Humans; Mouth Neoplasms; Tumor Microenvironment

Oral mucositis is the most common toxicity of chemoradiotherapy treatment of head and neck cancers. The present study was performed to evaluate the effect of a researched turmeric formulation on oral mucositis in patients receiving chemoradiotherapy for oral cancer.. This randomized double-blinded placebo-controlled trial included 60 patients with oral cancer who had undergone radical surgery. Patients were equally randomized into 3 arms. Bio-enhanced turmeric formulation (BTF) capsules (low dose [1 g/day] or high dose [1.5 g/day]) or placebo was administered daily for 6 weeks with concurrent chemoradiotherapy. Study endpoints included the impact of the treatment on chemoradiotherapy-induced oral mucositis along with dysphagia, oral pain, dermatitis, and weight loss.. The incidence of grade 3 toxicity of oral mucositis, oral pain, dysphagia, and dermatitis was significantly lower in patients who received BTF than placebo. Twenty-five and 20% patients in BTF 1 g/day (p = 0.011) and 1.5 g/day (p = 0.004) arms, respectively, developed grade 3 oral mucositis compared to 65% patients in the placebo arm. Thirty-five and 30% patients in BTF 1 g/day (p = 0.027) and 1.5 g/day (p = 0.011) arms, respectively, developed grade 3 oral pain compared to 70% patients in the placebo arm. Twenty-five and 20% patients in BTF 1 g/day (p = 0.025) and 1.5 g/day (p = 0.010) arms, respectively, developed grade 3 dysphagia compared to 60% patients in the placebo arm. Ten and 5% patients in BTF 1 g/day (p = 0.114) and 1.5 g/day (p = 0.037) arms. respectively, developed grade 3 dermatitis compared to 30% patients in the placebo arm. Patients under BTF supplementation experienced significantly less weight loss and greater compliance with treatment than placebo.. BTF (BCM-95®) can significantly reduce chemoradiotherapy-induced severe oral mucositis, dysphagia, oral pain, and dermatitis in oral cancer patients.. Clinical Trials Registry, India (Registration No. CTRI) (CTRI/2015/12/006413 dated December 4, 2015).

Topics: Chemoradiotherapy; Curcuma; Deglutition Disorders; Dermatitis; Double-Blind Method; Head and Neck Neoplasms; Humans; Mouth Neoplasms; Pain; Stomatitis; Weight Loss

Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.. A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.. Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.. The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.. Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.

Topics: Absorption, Physiological; Adult; Aged; Antineoplastic Agents; Curcumin; Cytokines; Double-Blind Method; Female; Humans; Inflammation; Male; Microbiota; Middle Aged; Mouth Neoplasms; Polyphenols; Saliva; Tumor Microenvironment

Turmeric extract and turmeric oil have shown chemoprotective effect against chemically-induced malignancies in experimental animals. They can reverse precancerous changes in oral submucous fibrosis in humans. The use of turmeric or Curcuma longa Linn as a spice and household remedy has been known to be safe for centuries. In view of the long term administration required for cancer prevention a Phase I clinical trial of turmeric oil (TO) was designed to study the safety and tolerance of TO in volunteers for a period of 3 months.. Nine healthy volunteers between 20 and 33 years of age were tested for haemoglobin, blood counts, liver and kidney functions, bleeding and clotting time and serum electrolytes initially and at 1 and 3 months of treatment. They were administered 0.6 ml of TO three times a day for 1 month and 1 ml in 3 divided doses for 2 months. The acute tolerability study on Day 1 was conducted in a Clinical Pharmacology daycare Unit. Blood pressure and pulse were recorded frequently on Day 1 and at 24, 48, 72 and 96 hours and fortnightly till 12 weeks. Volunteers were daily supervised for TO intake as well as for any side effects throughout the study period.. Nine volunteers were enrolled for the study. One discontinued on 3rd day for allergic skin rashes which, on discontinuation of TO, gradually disappeared by two weeks. Another discontinued on 7th day for intercurrent fever requiring antibiotic treatment. Seven volunteers completed the study. There was no effect of TO, in two doses, on pulse and blood pressure and no side effects in acute tolerability study on Day 1. There was no effect of TO intake on weight, blood pressure, symptoms and signs upto 12 weeks. There was no clinical, haematological, renal or hepatic-toxicity of TO at 1 month and 3 months. Serum lipids did not show significant change except in one volunteer (reversible).. In view of the potential for reversing oral submucous fibrosis, a precancerous condition for oral cancer, TO, can be recommended directly for a Phase II trial in patients.

Topics: Adult; Blood Cells; Blood Coagulation; Blood Pressure; Chemoprevention; Curcuma; Female; Healthy Volunteers; Humans; Medicine, Ayurvedic; Mouth Neoplasms; Oral Submucous Fibrosis; Plant Extracts; Safety; Time Factors; Water-Electrolyte Balance

Accumulating evidence indicates that curcumin (CUR) has anticancer properties in various cancers including oral squamous cell carcinoma (OSCC), but CUR is greatly restricted in clinical studies and applications due to its low bioavailability. Interestingly, the bioavailability of CUR was found to be significantly improved using loaded lipid nanoemulsions (NEs).. To investigate the effect of CUR-NEs on cell proliferation of OSCC HSC-3 cells in vitro, and explore the potential mechanism of this effect in a preliminary study.. CUR-NEs exhibited significantly cytotoxic effects on OSCC cells in a dose-dependent manner, compared with the control. The percentage of cells in proliferative phases (S + G2/M) was gradually decreased in a dose- or time-dependent manner caused by CUR-NEs. Moreover, CUR-NEs downregulated the protein expression of PI3K/Akt/mTOR and upregulated the expression of miR-199a that targeted PI3K in a dose- or time-dependent manner in OSCC cells. Importantly, CUR-NEs cloud effectively counteract the influence on cell proliferation of OSCC cells and the proliferative phases of cell cycle caused by miR-199a inhibitor a time-dependent manner.. This in vitro preliminary study indicated that CUR-NEs may be an effective therapeutic agent for OSCC. Such effects could be related to inhibition of OSCC cell proliferation by PI3K/Akt/mTOR suppression and miR-199a upregulation.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Head and Neck Neoplasms; Humans; MicroRNAs; Mouth Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TOR Serine-Threonine Kinases; Up-Regulation

Buccal drug administration may be chosen as a medication route to treat various diseases for local or systemic effects. This study proposes the development of a thermosensitive hydrogel containing curcumin-loaded lipid-core nanocapsules coated with chitosan to increase mucoadhesion, circumventing several limitations of this route of administration. Hydroxypropylmethylcellulose and Poloxamer

Topics: Animals; Carcinoma, Squamous Cell; Chickens; Chitosan; Curcumin; Female; Head and Neck Neoplasms; Hydrogels; Lipids; Mouth Neoplasms; Nanocapsules; Squamous Cell Carcinoma of Head and Neck; Swine

The efficacy of photodynamic therapy (PDT) is still limited by the inefficient utilisation of generated ROS in tumours due to cellular redox homeostasis. To improve the therapeutic efficacy for oral carcinoma, biomimetic cell membrane-coated mesoporous nanoplatform was tailored to interfere with cellular redox homeostasis for amplified PDT. In this study, CAL-27 cancer cell membrane (CM) was encapsulated onto the mesoporous silica NPs (MSN), which were preloaded with Chlorin e6 (Ce6) and Curcumin (Cur). The biomimetic nanoparticles displayed a size of around 120 nm, which had excellent cytotoxicity under a laser and increased uptake ability to tumour cell. After internalised by cancer cells, the released Cur could effectively disturb ROS-defence system by suppressing TrxR activity, and decreasing TrxR-2 expression (

Topics: Carcinoma; Cell Line, Tumor; Cell Membrane; Curcumin; Homeostasis; Humans; Mouth Neoplasms; Nanoparticles; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents; Reactive Oxygen Species

Until now, chemotherapy, which has a series of side effects, has been the most widely employed treatment for different types of cancer. However, bioactive products have been utilized as alternative medicines for tumors due to their bioactivities with low or no side effects in normal cells. This research reported for the first time that curcumin (CUR) and paclitaxel (PTX) have significant anti-cancer activity against normal human gingival fibroblast (HGF) and tongue squamous cell carcinoma fibroblast (TSCCF) cell lines. The results showed that CUR (13.85 µg mL

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; Humans; Mouth Neoplasms; Paclitaxel; Reactive Oxygen Species; Tongue Neoplasms

Human oral squamous cell carcinoma (OSCC) is the common head and neck malignancy in the world. While surgery, radiotherapy and chemotherapy are emerging as the standard treatment for OSCC patients, the outcome is limited to the recurrence and side effects. Therefore, patients with OSCC require alternative strategies for treatment. In this study, we aimed to explore the therapeutic effect and the mode of action of the novel curcumin analog, HO-3867, against human OSCC cells. We analysed the cytotoxicity of HO-3867 using MTT assay. In vitro mechanic studies were performed to determine whether MAPK pathway is involved in HO-3867 induced cell apoptosis. As the results, we found HO-3867 suppressed OSCC cells growth effectively. The flow cytometry data indicate that HO-3867 induce the sub-G1 phase. Moreover, we found that HO-3867 induced cell apoptosis by triggering formation of activated caspase 3, caspase 8, caspase 9 and PARP. After dissecting MAPK pathway, we found HO-3867 induced cell apoptosis via the c-Jun N-terminal kinase (JNK)1/2 pathway. Our results suggest that HO-3867 is an effective anticancer agent as its induction of cell apoptosis through JNK1/2 pathway in human oral cancer cells.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Head and Neck Neoplasms; Humans; Mouth Neoplasms; Piperidones; Squamous Cell Carcinoma of Head and Neck

GO-Y078, a new synthetic analogue of curcumin (CUR), has higher oral bioavailability and anticancer activity than CUR, but the oncostatic effect of GO-Y078 on oral squamous cell carcinoma (OSCC) is largely unknown.. In the present study, we examined the oncostatic properties and possible mechanisms of GO-Y078 on human SCC-9 and HSC-3 OSCC cells.. Our results provide new insights into the role of GO-Y078-induced molecular regulation in suppressing OSCC growth and suggest that GO-Y078 has potential therapeutic applications for OSCC.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; DNA; Head and Neck Neoplasms; Heme Oxygenase-1; Humans; Mouth Neoplasms; Transcription Factor AP-1; Transcriptional Activation

Oral malignancies have a significant effect on the quality of life among the affected patients. Curcumin is an antioxidant with a low bioavailability in the target tissue. Niosomes are carriers of increasing the therapeutic effects of drugs and reducing their side effects. This study aimed to determine the effective dose of curcumin niosome in the culture and then to compare its prophylactic effect in the form of mouthwash with that of its injectable form on oral cancer in rats.. This was an in-vitro and in-vivo study. Firstly, KB oral cancer cells and human umbilical vein endothelial cells (HUVEC) were treated in separate groups with free curcumin, curcumin-loaded niosomes, and the unloaded niosomes at four doses of 4, 8, 16, and 32 μg. The study rats were then divided into the following four groups: 1) no intervention, 2) only carcinogenic substance, 3) carcinogenic substance with curcumin-loaded niosome injection, and 4) carcinogenic substance with a mouthwash containing niosome.. At the cellular level, a dose of 16 μg after 24 h was selected as an effective dose. In the animal phase, the use of injectable curcumin niosome was observed to significantly prevent the development of severe forms of dysplasia.. In this in-vitro and in-vivo study, curcumin-loaded niosome was effective in preventing the development of severe forms of dysplasia and the inhibition of the growth of cancer cells.

Topics: Animals; Antioxidants; Curcumin; Endothelial Cells; Humans; Liposomes; Mouth Neoplasms; Mouthwashes; Quality of Life; Rats

Inhibition of Poly (ADP-ribose) Polymerases (PARP) results in the blocking of DNA repair cascades that eventually leads to apoptosis and cancer cell death. PARP inhibitors (PARPi) exhibit their actions either by inhibiting PARP-induced PARylation and/or by trapping PARP at the DNA damage site. But, the mechanism of PARPi-mediated induction of cellular toxicity via PARP-trapping is largely unknown.. The cellular toxicity of PARPi [Talazoparib (BMN) and/or Olaparib (Ola)] was investigated in oral cancer cells and the underlying mechanism was studied by using in vitro, in silico, and in vivo preclinical model systems.. The experimental data suggested that induction of DNA damage is imperative for the optimal effectiveness of PARPi. Curcumin (Cur) exhibited maximum DNA damaging capacity in comparison to Resveratrol and 5-Flurouracil. Combination of BMN + Ola induced cell death in Cur pre-treated cells at much lower concentrations than their individual treatments. BMN + Ola treatment deregulated the BER cascade, potentiated PARP-trapping, caused cell cycle arrest and apoptosis in Cur pre-treated cells in a much more effective manner than their individual treatments. In silico data indicated the involvement of different amino acid residues which might play important roles in enhancing the BMN + Ola-mediated PARP-trapping. Moreover, in vivo mice xenograft data also suggested the BMN + Ola-mediated enhancement of apoptotic potentiality of Cur.. Thus, induction of DNA damage was found to be essential for optimal functioning of PARPi and BMN + Ola combination treatment enhanced the apoptotic potentiality of Cur in cancer cells by enhancing the PARP-trapping activity via modulation of BER cascade.

Topics: Adenosine Diphosphate; Amino Acids; Animals; Apoptosis; Cell Line, Tumor; Curcumin; DNA; Humans; Mice; Mouth Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Resveratrol; Ribose

Conventional treatment resistance remains a significant problem in cancer care. Cancer stem cells might play a major role in treatment resistance, and as a result, basic stem cell pathways are instrumental in cancer. Sonic Hedgehog signaling has not been widely studied in oral cancer, and being one of the major cancer stem cell pathways, targeting it with natural compounds could open many opportunities in the treatment scenario.. The objective of the study was to identify the role of various natural compounds as an anti-cancer agent for oral cancer by targeting the Hedgehog signaling pathway.. The selection of natural compounds were identified through literature review and NPACT database. The protein (3M1N and 3MXW) and ligand molecules were retrieved through the PDB and PubChem database. To carry out docking experiments, the AutoDock 4.2 program was used to study the interaction between the identified protein and ligand.. Among the 13 identified natural compounds, the top three were selected based on their binding energy. The higher the binding energy on the negative side, the better the interaction formed between protein and ligand. The natural compound showing best results with 3M1N protein were Butein, Biochanin-A, and Curcumin, whereas, with 3MXW, Zerumbone, Curcumin, and Butein were identified.. The identified natural compounds have shown better binding energy to bind the Hh ligands in the absence/ presence of a known Sonic Hedgehog inhibitor. Based on the results, natural compounds can be utilized in the current treatment modality for oral cancer either as an individual anti-cancer agent or in combination with the known Sonic Hedgehog inhibitor to curb the increasing incidence rate. Yet, in-vitro evidence in lab setup is required.

Topics: Curcumin; Hedgehog Proteins; Humans; Ligands; Mouth Neoplasms; Signal Transduction

Oral cancer is the most common oral malignant tumor in Taiwan. Although there exist several methods for treatment, oral cancer still has a poor prognosis and high recurrence. FLLL32, a synthetic analog of curcumin with antitumor activity, is currently known to induce melanoma apoptosis and inhibit tumor growth in various cancers. However, few studies have examined the mechanisms of FLLL32 in oral cancer. In this study, we explore whether FLLL32 induces apoptosis in oral cancer. We determined that FLLL32 can inhibit the cell viability of oral cancer. Next, we analyzed the effect of FLLL32 on the cell cycle of oral cancer cells and observed that the proportion of cells in the G2/M phase was increased. Additionally, annexin-V/PI double staining revealed that FLLL32 induced apoptosis in oral cancer cells. Data from the Human Apoptosis Array revealed that FLLL32 increases the expression of cleaved caspase-3 and heme oxygenase-1 (HO-1). FLLL32 activates proteins such as caspase-8, caspase-9, caspase-3, PARP, and mitogen-activated protein kinases (MAPKs) in apoptosis-related molecular mechanisms. Moreover, by using MAPK inhibitors, we suggest that FLLL32 induces the apoptosis of oral cancer cells through the p38 MAPK signaling pathway. In conclusion, our findings suggest that FLLL32 is a potential therapeutic agent for oral cancer by inducing caspase-dependent apoptosis and HO-1 activation through the p38 pathway. We believe that the activation of HO-1 and the p38 pathway by FLLL32 represent potential targets for further research in oral cancer.

Topics: Carcinoma, Squamous Cell; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Heme Oxygenase-1; Humans; MAP Kinase Signaling System; Mouth Neoplasms

Concurrent use of DNA damaging agents with PARP inhibitors contribute to the effectiveness of the anticancer therapy. But there is a dearth of reports on the antiangiogenic effects of PARP inhibitors and the suppression of angiogenesis by this drug combination is not yet reported. For the successful development of cancer therapeutics, anti-cancer drugs ought to have anti-angiogenic potentiality along with their DNA damaging abilities. In this current piece of work, we investigated the in vitro and in ovo anti-angiogenic effect of Curcumin and Veliparib (a PARP inhibitor) in oral cancer. Recent evidences suggest an involvement of the NECTIN-4 in cancer angiogenesis and the exact molecular pathway of this involvement remains to be delineated. We observed that the soluble NECTIN-4 secreted from H357 oral cancer cells enhanced the angiogenesis of endothelial cells (HUVECs) and this was inhibited by Curcumin-Veliparib combination. NECTIN-4 enhanced vascularization, induced vasodilation and triggered the angiogenic sprouting via endothelial tip cell filopodia. Data indicated that NECTIN-4 mediated angiogenesis is associated with PI3K-AKT-mediated nitric oxide (NO) formation. A noticeable increase in the NO enhanced epithelial NO level through HIF-1α mediated iNOS activation. We observed that increased NO enhanced the NECTIN-4 mediated eNOS expression and thereby elicited further angiogenesis. Curcumin antagonised the NECTIN-4-induced angiogenesis through inhibition of PI3K-AKT mediated eNOS pathway and Veliparib synergized the effect of Curcumin. Our observations indicate that NO is cardinal in inducing NECTIN-4 mediated angiogenesis in H357 cells. Thus, Curcumin-Veliparib combination suppresses angiogenesis through deregulation of the PI3K-AKT-eNOS pathway downstream to the NECTIN-4.

Topics: Benzimidazoles; Cell Adhesion Molecules; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned; Curcumin; Drug Synergism; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mouth Neoplasms; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Superoxide Dismutase

Topics: Apoptosis; Autophagy; Cell Survival; Curcumin; Head and Neck Neoplasms; Humans; Membrane Potential, Mitochondrial; Mouth Neoplasms; Signal Transduction

Apart from inducing catalytic inhibition of PARP-1, PARP inhibitors can also trap PARP proteins at the sites of DNA damage and forming toxic PARP-DNA complexes. These complexes obstruct the DNA repair process, resulting in cancer cell death. To study the detailed mechanism of anti-cancer action through PARP trapping, we have treated oral cancer cells (H-357) with curcumin (Cur), olaparib (Ola) and their combination (Cur + Ola). Cur + Ola treatment triggered the expressions of PARP-1 and adenomatous polyposis coli (APC) and down regulated other base excision repair (BER) proteins in the chromatin fraction but not in the nuclear fraction. Cur + Ola treatment inhibited PARylation, altered interaction of PARP-1 with representative BER proteins and arrested cells in S-phase. We have for the first time provided direct evidence and measured the cellular PARP-1 trapping potentiality of Ola in Cur pretreated H-357 cells. Unchanged cellular PARP-1 trapping, unaltered expression of BER proteins and BER activity were found in APC silenced H-357 cells, which further confirmed that the DNA damage/repair response was APC-dependent. Interestingly, complete abolishment of the chromatin remodeler 'amplified in Liver Cancer 1' (ALC1), decreased expression of Histone H3 and histone acetyltransferase (P300) was noted in chromatin of Cur + Ola treated cells. Their expressions remained unchanged in APC silenced cells. Cur + Ola also altered the interaction of ALC1 with BER proteins including APC. Thus, the present study reveals that Cur + Ola treatment increased oral cancer cell death not only through catalytic inhibition of PARP-1 but also predominantly through PARP-1 trapping and indirect inhibition of chromatin remodeling.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Chromatin Assembly and Disassembly; Curcumin; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors

Although Olaparib (Ola, a PARP-inhibitor), in combination with other chemotherapeutic agents, was clinically approved to treat prostate cancer, but cytotoxicity, off-target effects of DNA damaging agents limit its applications in clinic. To improve the anti-cancer activity and to study the detailed mechanism of anti-cancer action, here we have used bioactive compound curcumin (Cur) in combination with Ola. Incubation of Ola in Cur pre-treated cells synergistically increased the death of oral cancer cells at much lower concentrations than individual optimum dose and inhibited the topoisomerase activity. Short exposure of Cur caused DNA damage in cells, but more increased DNA damage was noticed when Ola has incubated in Cur pre-treated cells. This combination did not alter the major components of homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways but significantly altered both short patch (SP) and long patch (LP) base excision repair (BER) components in cancer cells. Significant reduction in relative luciferase activity, expression of BER components and PARylation after Cur and Ola treatment confirmed this combination inhibit the BER activity in cells. Reduction of PARylation, decreased expression of BER components, decreased tumor volume and induction of apoptosis were also noticed in Cur + Ola treated Xenograft mice model. The combination treatment of Cur and Ola also helped in recovering the body weight of tumor-bearing mice. Thus, Cur + Ola combination increased the oral cancer cells death by not only causing the DNA damage but also blocking the induction of BER activity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Curcumin; DNA Damage; DNA Repair; Drug Synergism; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Oral squamous cell carcinoma (OSCC) is among the most frequent oral cancers in individuals under 40. Documents have endorsed that a diet enriched with fruit and vegetables can banish the risk of developing major cancers. This study aimed to evaluate the effects of different concentrations of four medicinal herbs including saffron, ginger, cinnamon and curcumin on OSCC cell line.. Having obtained the aqueous extract of the four herbs, they were administered on OSCC cell lines per se and in dual, triple, and quadruple combinations. Their effects were measured in different concentrations and in 24 and 48 hours by using MTT assay.. The minimum and maximum effective concentrations were respectively 108 and 217 mg/ml for curcumin with IC30 of 77mg/ml, 108 and 270 mg/ml for ginger with IC30 of 58 mg/ml, 2 and 10 mg/ml for saffron with IC30 of 1.9 mg/ml, and 5 and 40 mg/ml for cinnamon with IC30 of 3.3 mg/ml. The best effect of the combinations was seen for cinnamon-saffron after both 24 and 48 hours and the four herbs combination after 48 hours.. Although all the four herbs were effective on OSCC cell line, the strongest extract was saffron, followed by cinnamon. Combination of cinnamon-saffron and combination of the four herbs showed maximum effects. These findings suggest that traditional medicinal herbs may potentially contribute to oral cancer treatment; providing new windows for the development of new therapeutic strategies for OSCC.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Cinnamomum zeylanicum; Crocus; Curcumin; Humans; Mouth Neoplasms; Plant Extracts; Squamous Cell Carcinoma of Head and Neck; Zingiber officinale

Current oral squamous cell carcinoma chemotherapies demonstrate off-target toxicity, which could be reduced by local delivery. Curcumin acts via many cellular targets to give anti-cancer properties; however the bioavailability is hindered by its physicochemical characteristics. The incorporation of curcumin into emulgel systems could be a promising approach for its solubilization and delivery. The aim of this work was to develop emulgel systems containing curcumin for the treatment of oral cancer. The emulgels containing curcumin were prepared with poloxamer 407, acrylic acid derivatives, oil phase (sesame oil or isopropyl myristate). The more stable system was evaluated for mechanical and rheological properties, as well as, the in vitro drug release profile, permeation and cytotoxic potential to oral mucosa models. The flow-throw system evidenced that the formulations could keep 5 min over porcine oral mucosa. Emulgel showed pseudoplastic behavior and a gelation temperature of 33 °C, which ensure their higher consistency. In addition, 70% of the incorporated curcumin was released within 24 h in an in vitro drug release study and could permeate porcine oral mucosa. Monolayers cultures and tissue-engineered models showed the selectivity of the drug and systems for tumor cells. The physicochemical properties, subsequent release and permeation of curcumin to selectivity kill cancer cells could be improved by the incorporation into emulgel systems.

Topics: Animals; Carcinoma, Squamous Cell; Curcumin; Drug Delivery Systems; Head and Neck Neoplasms; Mouth Mucosa; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; Swine

Oral cancer (OC) is a serious health problem. Surgery is the best method to treat the disease but might reduce the quality of life of patients. Photodynamic therapy (PDT) may enhance quality of life but with some limitations. Therefore, the development of a new strategy to facilitate PDT effectiveness has become crucial. ATP-binding cassette G2 (ABCG2) is a membrane protein-associated drug resistance and stemness in cancers. Here, we examined whether ABCG2 plays an important role in regulating the treatment efficacy of PDT and whether ABCG2 inhibition by natural compounds can promote the effect of PDT in OC cells. Several head and neck cancer cells were utilized in this study. OECM1 and SAS cells were selected to investigate the relationship between ABCG2 expression and protoporphyrin IX (PpIX) accumulation. Western blot analysis, flow cytometry analysis, and survival probability were performed to determine PDT efficacy and cellular stemness upon treatment of different dietary compounds, including epigallocatechin gallate (EGCG) and curcumin. In this study, we found that ABCG2 expression varied in OC cells. Hypoglycemic culture for SAS cells enhanced ABCG2 expression as higher ABCG2 expression was associated with lower PpIX accumulation and cellular stemness in OC cells. In contrast, suppression of ABCG2 expression by curcumin and tea polyphenol EGCG led to greater PpIX accumulation and enhanced PDT treatment efficiency in OC cells. In conclusion, ABCG2 plays an important role in regulating the effect of PDT. Change in glucose concentration and treatment with natural compounds modulated ABCG2 expression, resulting in altered PDT efficacy for OC cells. These modulations raise a potential new treatment strategy for early-stage OCs.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Catechin; Cell Line, Tumor; Cell Survival; Curcumin; Gefitinib; Humans; Kaplan-Meier Estimate; Mouth Neoplasms; Neoplasm Proteins; Photochemotherapy; Photosensitizing Agents

Curcumin (Cur), a natural product, has been shown to have anti-tumor activities in many human cancer cells. Gefitinib (Gef) is a clinical drug for cancer patients. However, there is no available information to show whether Gef/Cur nanoparticles (NPs) increased cell apoptosis and anti-tumor effects on xenograft mice model in vivo. In this study, γ-polyglutamic acid-coated nanoparticles loaded with Gef and Cur (γ-PGA-Gef/Cur NPs) were developed and its physicochemical properties and antitumor effects were investigated in vitro and in vivo. The γ-PGA-Gef/Cur NPs showed 548.5 ± 93.7 nm in diameter and -40.3 ± 3.87 mV on surface charge. The loading efficiencies of Gef and Cur were 89.5 and 100%, respectively. γ-PGA-Gef/Cur NPs could be internalized into SAS cells and significantly decreased total cell viability of SAS cells. Western blotting results indicated that both free Gef/Cur and γ-PGA-Gef/Cur NPs induced apoptotic cell death via caspase- and mitochondria-dependent pathways. In vivo studies indicated that treatments of PLGA NPs, free Gef/Cur, and γ-PGA-Gef/Cur NPs did not significantly affect appearances and bodyweights of mice. But the γ-PGA-Gef/Cur NPs significantly suppressed tumor size when comparing to free Gef/Cur-treated group. The nanoparticles developed in this study may be used as a potential therapy for oral cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Curcumin; Gefitinib; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Nanoparticles; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

Head and neck squamous cell carcinoma represents the sixth most common cancer. As a result of field cancerization, second primaries and recurrences are high. Hence, research has focused on chemoprevention. Curcumin, a polyphenol compound with anticarcinogenic properties, is one such promising nutraceutical. As poor bioavailability limits curcumin's use, a novel gum formulation was tested allowing for direct mucosal absorption into the bloodstream. This preliminary study validates curcumin gum efficacy by assessing release and transmucosal absorption, along with measuring its effects on serum cytokine levels.. Clinical trial.. Protocols consisting of initial chew (chewing gum for 30 minutes) and revised chew (alternating chewing and parking gum against buccal mucosa for 30 minutes) were tested in healthy volunteers. High-performance liquid chromatography measured remnant curcumin in chewed gum, serum, and saliva. Serum levels were assayed for 15 proinflammatory cytokines via multiplex analysis.. Revised chew samples demonstrated significantly higher curcumin release and absorption (P = .0078). Curcumin serum levels were significantly higher at 4 hours in samples > 2.0 g of curcumin release (P = .01). As saliva levels decreased, a concurrent increase in serum levels was observed, with no significance in the inverse relationship (P = .1423). When evaluating differences between gender, race, and age, the Asian population showed significantly lower curcumin release and serum levels (P = .009). CXCL1 (GRO-α) and TNF-α were significantly decreased in serum after chewing the gum (P = .036, P < .001, respectively).. Enhanced mucosal contact appears critical in improving curcumin release and absorption. CXCL1 and TNF-α both represent potential biomarkers for the future study of curcumin chemoprevention.. 2b Laryngoscope, 129:1597-1603, 2019.

Topics: Adult; Aged; Biological Availability; Biomarkers; Chewing Gum; Chromatography, High Pressure Liquid; Curcumin; Cytokines; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Saliva; Squamous Cell Carcinoma of Head and Neck; Time Factors

Numerous studies support the use of herbal medicine or natural products for chemotherapy in human cancers. Reports have associated curcumin (CUR), dimethoxy curcumin (DMC) and bisdemethoxycurcumin (BDMC) with numerous biological activities including anticancer activities, but no available information have shown that these induced apoptotic cell death and autophagy in human oral cancer cells. In the present study, we investigated the effect of CUR, DMC and BDMC on the cell viability, apoptotic cell death, reactive oxygen species (ROS), Ca[Formula: see text], mitochondria membrane potential (MMP) and caspase activities using flow cytometry assay and autophagy by monodansylcadaverine (MDC) and acridine orange (AO) staining in human oral cancer SAS cells. Results indicated that CUR, DMC and BDMC decreased total viable cell number through the induction of cell autophagy and apoptosis in SAS cells. Cells were pretreated with N-acetyl-cysteine (NAC), 3-methyladenine (3MA), rapamycin and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methylketone (Z-VAD-fmk) and then were treated with CUR, DMC and BDMC that led to increased total viable cell number when compared to CUR, DMC and BDMC treatments only. Results indicated induced apoptotic cell death through ROS, mitochondria-dependent pathway and induction of cell autophagy. Based on those observations, we suggest that CUR, DMC and BDMC could be used as a potential anticancer agent in human oral cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Curcumin; Humans; Mitochondria; Mouth Neoplasms; Reactive Oxygen Species

Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents, curcumin and metformin are reported to exhibit chemopreventive properties, in vitro as well as in patients with oral cancer. In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40-100-fold) and protein levels (P ≤ 0.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4 mm

Topics: 4-Nitroquinoline-1-oxide; AC133 Antigen; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Chemoprevention; Curcumin; Female; Hyaluronan Receptors; Hypoglycemic Agents; Metformin; Mice, Inbred C57BL; Mouth; Mouth Neoplasms; Neoplastic Stem Cells

Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 μM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 μM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 μM of curcumin (50% and 40%, respectively, p < 0.05). Using spheroids, we observed that curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Animals; Apoptosis; Carcinogenesis; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line; Cell Movement; Cell Proliferation; Curcuma; Curcumin; Humans; Keratinocytes; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; NIH 3T3 Cells; Spheroids, Cellular; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Diphenyldifluoroketone (EF24) is a curcumin analog that has been demonstrated to improve anticancer activity; however, its therapeutic potential and mechanisms in oral cancer remain unknown. In the present study, the effect of EF24 on apoptosis induction and its potential underlying mechanism in the CAL‑27 human OSCC cell line was investigated. To achieve this, various concentrations of cisplatin or EF24 were administrated to CAL‑27 cells for 24 h, and cell viability, apoptotic DNA fragmentation, and cleaved caspase 3 and 9 levels were evaluated. To investigate the potential underlying mechanism, the levels of mitogen‑activated protein kinase kinase 1 (MEK1) and extracellular signal‑regulated kinase (ERK), two key proteins in the mitogen‑activated protein kinase/ERK signaling pathway, were additionally examined. The results indicated that EF24 and cisplatin treatment decreased cell viability. EF24 treatment increased the levels of activated caspase 3 and 9, and decreased the phosphorylated forms of MEK1 and ERK. Sequential treatments of EF24 and 12‑phorbol‑13‑myristate acetate, a MAPK/ERK activator, resulted in a significant increase of activated MEK1 and ERK, and reversed cell viability. These results suggested that EF24 has potent anti‑tumor activity in OSCC via deactivation of the MAPK/ERK signaling pathway. Further analyses using animal models are required to confirm these findings in vivo.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Curcumin; Humans; MAP Kinase Signaling System; Mouth Neoplasms

We studied the effect of grape seed extract Burgund Mare (BM) on oral carcinogenesis and compared it with that of curcumin (CU). Wistar rats were divided into six groups (n = 10): 4-nitro-quinoline-1-oxide (4NQO) oral carcinogenesis was induced to groups 1 - 5; groups 2 and 3 received BM and CU respectively during initiation and groups 4 and 5 BM and CU during post-initiation of carcinogenesis; group 6 represented the negative control group. Total malondialdehyde (MDA) and reduced glutathione (GSH) were assayed fluorometrically in oral tissue (gingival, jugal, palatal, lingual mucosa) and serum. Histopathological exam was performed and a dysplasia score given to each oral mucosal lesion. Ki67, cyclin D1, p63, Bcl2 and p53 were immunohistochemically evaluated. BM and CU reduced tissue MDA values elevated by 4NQO (P = 0.000). The difference between CU and BM effect was significant in the initiation (P = 0.02) but not in the post-initiation phase of carcinogenesis (P = 0.58). Tissue GSH levels decreased by 4NQO (P < 0.001) were not significantly modified by BM or CU. Serum MDA levels increased by 4NQO (P = 0.000) were significantly lowered by CU (P = 0.04) and BM (P = 0.04) during initiation and by CU during post-initiation of carcinogenesis (P = 0.01). CU was more potent than BM during post-initiation of carcinogenesis (P = 0.01). Serum GSH lowered by 4NQO (P = 0.55) was significantly decreased by BM and CU (P < 0.012), with no significant difference between groups receiving BM or CU. Moderate dysplasia was the most advanced dysplasia induced and gingival localization the most frequent. Both BM and CU lowered dysplasia scores, with BM being the most efficient during post-initiation of carcinogenesis (P = 0.001). Ki67, cyclin D1, p63, Bcl2 and p53 expression increased with dysplasia scores. BM showed chemopreventive properties during initiation and post-initiation of oral carcinogenesis, reducing local and general oxidative stress and the intensity of dysplasia. During post-initiation of carcinogenesis BM and CU exhibited similar effects.

Topics: Animals; Biological Products; Carcinogenesis; Chemoprevention; Curcumin; Glutathione; Grape Seed Extract; Male; Malondialdehyde; Mouth Mucosa; Mouth Neoplasms; Rats; Rats, Wistar

Oral cancer is the sixth most common cancer worldwide and 90% of oral malignancies are caused by oral squamous cell carcinoma (OSCC). Curcumin, a phytocompound derived from turmeric (Curcuma longa) was observed to have anti-cancer activity which can be developed as an alternative treatment option for OSCC. However, OSCC cells with various clinical-pathological features respond differentially to curcumin treatment.. Intracellular copper levels have been reported to correlate with tumor pathogenesis and affect the sensitivity of cancer cells to cytotoxic chemotherapy. We hypothesized that intracellular copper levels may affect the sensitivity of oral cancer cells to curcumin.. We analysed the correlation between intracellular copper levels and response to curcumin treatment in a panel of OSCC cell lines derived from oral cancer patients. Exogenous copper was supplemented in curcumin insensitive cell lines to observe the effect of copper on curcumin-mediated inhibition of cell viability and migration, as well as induction of oxidative stress and apoptosis. Protein markers of cell migration and oxidative stress were also analysed using Western blotting.. Concentrations of curcumin which inhibited 50% OSCC cell viability (IC. Supplement of copper significantly enhanced the inhibitory effect of curcumin treatment on migration and viability of oral cancer cells. Together, these findings provide molecular insight into the role of copper in overcoming insensitivity of oral cancer cells to curcumin treatment, suggesting a new strategy for cancer therapy.

Topics: Adjuvants, Pharmaceutic; Antigens, CD; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Cadherins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Copper; Curcuma; Curcumin; Dietary Supplements; Drug Synergism; Epithelial-Mesenchymal Transition; Humans; Mouth Neoplasms; Phytotherapy; Plant Extracts; Trace Elements; Vimentin

To investigate the effects of curcumin and paclitaxel on proliferation and apoptosis of human oral squamous carcinoma cell line CAL27.. CAL27 cells were cultured and treated with different concentrations of curcumin and paclitaxel separately or in combination for 24, 48 and 72 h. The cell proliferation was evaluated by MTT assay, and cell apoptosis was detected by Tunel staining. Expression of Bcl-2, Bax, and active caspase-3 were analyzed by Western blot. The data were analyzed with SPSS 11.0 software package.. Compared with the effects of curcumin or paclitaxel, combined treatment of both drugs significantly inhibited cell growth, induced cell apoptosis, decreased the expression of Bcl-2 and the ratio of Bcl-2/Bax, and increased the expression of Bax and active caspase-3 in CAL 27 cells.. Combined treatment of Curcumin and Paclitaxel significantly inhibits cell growth and mediated cell apoptosis compared with that of either single drug.

Topics: Apoptosis; bcl-2-Associated X Protein; Carcinoma, Squamous Cell; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Mouth Neoplasms; Paclitaxel; Proto-Oncogene Proteins c-bcl-2

Curcumin has therapeutic potential in preventing several types of cancer, including colon, liver, prostate, and breast. The goal of this study was to evaluate the chemopreventive activity of systemically administered curcumin on oral carcinogenesis induced by 4-nitroquinolone-1-oxide (4-NQO). A total of 50 male albino rats, Rattus norvegicus, (Holtzman), were divided into five groups (n = 10 per group). Four of these groups were exposed to 50 ppm 4-NQO in their drinking water ad libitum for 8 or 12 weeks, two groups were treated with curcumin by oral gavage at 30 or 100 mg/kg per day, and one group was treated with corn oil (vehicle) only. The negative control group was euthanized at baseline. Tongues of all animals were removed after euthanasia and used in the subsequent analysis because the tongue is the primary site of carcinogenesis in this model. Descriptive histological analysis and immunohistochemistry for PCNA, Bcl-2, SOCS1 e-3, and STAT3 were performed to assess the oncogenic process. The gene expression of Vimentin, E-cadherin, N-cadherin, or TWIST1 was assessed using RT-qPCR as a representative of epithelial-mesenchymal transition (EMT) events. The administration of curcumin at 100 mg/kg during the 12 weeks markedly decreased the expression of PCNA, Bcl-2, SOCS1 e -3, and STAT3. Curcumin also minimized the cellular atypia under microscopic analysis and diminished the expression of the genes associated with EMT. These findings demonstrate that the systemic administration of curcumin has chemopreventive activity during oral carcinogenesis induced by 4-NQO.

Topics: 4-Nitroquinoline-1-oxide; Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinogens; Corn Oil; Curcumin; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Gene Expression; Male; Mouth Neoplasms; Quinolones; Rats; Tongue

Epithelial-mesenchymal transition (EMT) and invasion play a critical role in cancer progression and metastasis. We have shown that low E-cadherin and high Twist expression are significantly correlated with prognostic survival prediction in oral squamous cell carcinoma (OSCC). This study aimed to determine the anti-invasive effect of curcumin on the expression of matrix metalloproteinases (MMPs) and of EMT regulators in OSCC.. SCC-25 cells were treated with curcumin, and cell proliferation, invasion, and expression of MMPs and EMT regulators were assessed for cell viability by trypan blue exclusion, for invasion by Matrigel invasion chamber, and for EMT regulators and MMP changes in the levels of proteins by immunoblotting.. Our data showed that curcumin treatment not only decreased the expression of MMP-2 and MMP-9 to inhibit invasiveness in oral cancer but also modulated the expression of EMT markers, such as Snail, Twist, and E-cadherin, and induced p53 expression that is crucial to EMT repression.. Curcumin has the potential to become an adjunctive regimen for the prevention of cancer progression and metastasis in oral cancer.

Topics: Cadherins; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Disease Progression; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mouth Neoplasms; Neoplasm Invasiveness; Tumor Suppressor Protein p53

Mucoadhesive nanoparticles loaded with curcumin were developed as a new approach to deliver curcumin for the local treatment of oral cancer. PCL nanoparticles coated with chitosan displaying different molar masses were prepared by using the nanoprecipitation technique. The mucoadhesive properties of nanoparticle suspensions were demonstrated by their strong ability to interact with the glycoprotein mucin through electrostatic interactions. Similar permeation profiles of curcumin loaded in uncoated and chitosan-coated nanoparticles across porcine esophageal mucosa were verified. Curcumin concentrations retained in the mucosa suggest the possibility of a local effect of the drug. In vitro studies demonstrated that free curcumin.and curcumin loaded into nanoparticles coated with chitosan caused significant reduction of SCC-9 human oral cancer cell viability in a concentration and time-dependent manner. However, no significant cell death was observed after 24 h of treatment with unloaded nanoparticles coated with chitosan. In addition, curcumin-loaded nanoparticles showed reduced cytotoxicity, when compared with the free drug. Therefore, chitosan-coated PCL nanoparticles may be considered a promising strategy to deliver curcumin directly into the oral cavity for the treatment of oral cancer.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chitosan; Curcumin; Esophagus; Humans; Mouth Neoplasms; Mucins; Nanoparticles; Swine

We report results on the use of organically modified silica nanoparticles (SiNp) as a vehicle for the delivery of curcumin in human oral cancer cells for improvement of uptake and phototoxicity. Nanoformulated drug (curcumin-SiNp complex) was prepared by postloading curcumin in SiNp, and the complex was soluble in aqueous solution. Cellular uptake studied by fluorescence microscopy and spectroscopy showed that curcumin accumulation was higher when cells were incubated with curcumin-SiNp complex as against free curcumin. Studies carried out on incubation time-dependent cytotoxicity, inhibition of NF-κB activity, suppression of NF-κB-regulated proteins involved in invasion (MMP-9), angiogenesis (VEGF), and inflammation (TNF-α) showed that curcumin-SiNp leads to significant improvement over free curcumin in dark as well as on exposure to light.

Topics: Antineoplastic Agents, Phytogenic; Cell Death; Curcumin; Drug Delivery Systems; Humans; Matrix Metalloproteinase 9; Microscopy, Fluorescence; Mouth Neoplasms; Nanoparticles; Neoplasms, Squamous Cell; NF-kappa B; Photochemotherapy; Silicon Dioxide; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

The anticancer effect of curcumin has been widely reported. However, whether curcumin can enhance the radiosensitivity of human oral squamous cell carcinoma (OSCC) remains to be elucidated. The aim of the present study was to evaluate the efficacy of curcumin combined with radiation against OSCC. SAS cells were transfected with the luciferase gene (luc) and named SAS/luc. NF-κB/DNA binding activity, the surviving fraction and NF-κB-regulated effector protein expression were determined by electrophoretic mobility shift assay, clonogenic survival assay and western blotting, respectively. The therapeutic efficacy was evaluated in SAS/luc tumor-bearing mice by caliper measurement and bioluminescence imaging. Curcumin enhanced SAS/luc radiosensitivity through the inhibition of radiation-induced NF-κB activity and expression of effector proteins both in vitro and in vivo. With 4 Gy or greater radiation doses, synergistic effects of curcumin were observed. The combination group (curcumin plus radiation) had significantly better tumor control compared with that of curcumin or radiation alone. No significant body weight change of mice was found throughout the entire study. In conclusion, curcumin is a radiosensitizer against OSCC with negligible toxicity.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Combined Modality Therapy; Curcumin; Electrophoretic Mobility Shift Assay; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mouth Neoplasms; NF-kappa B; Radiation Tolerance; Transfection; Xenograft Model Antitumor Assays

Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.

Topics: Carcinoma, Squamous Cell; CCAAT-Enhancer-Binding Protein-beta; Cell Line, Tumor; Curcumin; Epidermal Growth Factor; Humans; MicroRNAs; Mouth Mucosa; Mouth Neoplasms; Proto-Oncogene Proteins c-akt; Signal Transduction; Up-Regulation

Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer worldwide, accounts for approximately 600,000 new cases per year. The mobile tongue is the most common site for oral cancer and is associated with a poorer survival than other HNSCC sites. Standard therapeutic strategies have failed to significantly improve survival rates that have remained around 50% over the past four decades. In the last decade intense investigations on oral cancer highlighted the mandatory role of the tumor microenvironment (TME), in addition to the genetic aberrations and molecular biology changes within the cancer cells. Furthermore, the molecular crosstalk between cancer cells and TME components (i.e., cancer-associated fibroblasts, inflammatory pro-tumorigenic cells, etc.) has a crucial role in growth, invasion, spread and metastases of the cancer cells and consequently leads to poor prognosis. Recent studies suggest that plant-derived dietary agents nutraceuticals, especially curcumin and green tea, have the advantage to combat both malignant cells and TME components, unlike standard anti-cancer protocols that target only cancer cells. However, due to a very low bioavailability, nutraceuticals do not currently constitute an integral part of these protocols. Ongoing developments in nanotechnology for improved delivery are expected to overcome their challenging pharmacokinetics.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Curcumin; Dietary Supplements; Head and Neck Neoplasms; Humans; Mouth Neoplasms; Nanotechnology; Prognosis; Squamous Cell Carcinoma of Head and Neck; Survival Rate; Tea; Tumor Microenvironment

Epidermal growth factor receptor (EGFR) is an effective molecular target of anti-cancer therapies. Curcumin is known to inhibit growth, invasion and metastasis by downregulating EGFR expression in some cancer cells. However, the mechanism underlying the effect of curcumin in human oral squamous cell carcinoma (OSCC) remains unclear. In this study, we investigated the efficacy of curcumin on proliferation and invasion in SCC-25 cell line. We also explored the effect of curcumin on the activition of EGFR and its downstream signaling molecules Akt, ERK1/2 and STAT3. Furthermore, we examined the inhibition effect of curcumin on EGF-induced EGFR phosphorylation and SCC-25 cells invasion. Our results showed that curcumin inhibited SCC-25 cells proliferation and induced G2/M phase arrest in a dose-dependent manner. Curcumin also inhibited SCC-25 cells invasion and downregulated MMP-2, MMP-9, uPA and uPAR expression. We further revealed that curcumin regulated the p-EGFR and EGFR downstream signaling molecules including Akt, ERK1/2 and STAT3. Finally, our data showed that crucumin reduced the EGF-induced phosphorylation of EGFR and suppressed EGF-triggered SCC-25 cells invasion. Taken together, our results suggest that curcumin reduced SCC-25 cells proliferation and invasion through inhibiting the phosphorylation of EGFR and EGFR downstream signaling molecules Akt, ERK1/2 and STAT3.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; G2 Phase Cell Cycle Checkpoints; Humans; Mouth Neoplasms; Neoplasm Invasiveness; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor

Curcumin, a phytochemical derived from the rhizome of Curcuma longa, has shown anticancer effects against a variety of tumors. In the present study, we investigated the effects of curcumin on the miR-9 expression in oral squamous cell carcinoma (OSCC) and explored the potential relationships between miR-9 and Wnt/β-catenin pathway in curcumin-mediated OSCC inhibition in vitro. As the results shown, the expression levels of miR-9 were significantly lower in clinical OSCC specimens than those in the adjacent non-tumor tissues. Furthermore, our results indicated that curcumin inhibited OSCC cells (SCC-9 cells) proliferation through up-regulating miR-9 expression, and suppressing Wnt/β-catenin signaling by increasing the expression levels of the GSK-3β, phosphorylated GSK-3β and β-catenin, and decreasing the cyclin D1 level. Additionally, the up-regulation of miR-9 by curcumin in SCC-9 cells was significantly inhibited by delivering anti-miR-9 but not control oligonucleotides. Downregulation of miR-9 by anti-miR-9 not only attenuated the growth-suppressive effects of curcumin on SCC-9 cells, but also re-activated Wnt/β-catenin signaling that was inhibited by curcumin. Therefore, our findings would provide a new insight into the use of curcumin against OSCC in future.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; MicroRNAs; Mouth Neoplasms; Structure-Activity Relationship

Curcumin (diferuloyl methane) and its naturally occurring analogs viz. demethoxy, bisdemethoxy and cyclocurcumin, present in rhizomes of curcuma species turmeric, have been shown to inhibit the proliferation of a wide variety of tumor cells. Target nuclear protein HPV 16 E6 (PDB ID: 2fk4) is the major protein actively participating in oral and cervical cancers. In silico studies indicate that curcumin and its natural analogs have effective binding with different active sites on HPV 16 E6 protein, ideal target for restoring the tumor suppressor function of p53 and thus allowing the apoptosis of infected cells. The main limitation in the use of curcuminoids as therapeutic agents is their low bioavailability. Since piperine is known to enhance curcumin bioavailability to more than two thousand times by inhibiting its efflux, a conjugate of curcumin-piperic acid was also used. Although curcumin has been found to have strongest binding with this target and the two curcuminoids, demethoxy and bisdemethoxy curcumin have lower but comparable affinity, chlorogenic acid amongst the naturally occurring analogs has been found to have best binding affinity amongst all the analogs. Although curcumin-piperoyl conjugate does not show very encouraging results, it is likely to have potential activity in vitro and in vivo. These results throw light on the SAR of curcuminoids, leading to future designing of potent, non-toxic drugs for oral and cervical cancers.

Topics: Catalytic Domain; Chemoprevention; Chlorogenic Acid; Curcumin; Female; Humans; Hydrogen Bonding; Ligands; Molecular Docking Simulation; Mouth Neoplasms; Oncogene Proteins, Viral; Repressor Proteins; Thermodynamics; Uterine Cervical Neoplasms

Curcumin is a polyphenolic compound which possesses anticancer potential. It has been shown to induce cell death in a variety of cancer cells, however, its effect on CAL27‑cisplatin-resistant human oral cancer cells (CAR cells) has not been elucidated to date. The low water solubility of curcumin which leads to poor bioavailability, however, has been highlighted as a major limiting factor. In this study, we utilized water-soluble PLGA curcumin nanoparticles (Cur-NPs), and investigated the effects of Cur-NPs on CAR cells. The results showed Cur-NPs induced apoptosis in CAR cells but exhibited low cytotoxicity to normal human gingival fibroblasts (HGFs) and normal human oral keratinocytes (OKs). Cur-NPs triggered DNA concentration, fragmentation and subsequent apoptosis. Compared to untreated CAR cells, a more detectable amount of Calcein-AM accumulation was found inside the treated CAR cells. Cur-NPs suppressed the protein and mRNA expression levels of MDR1. Both the activity and the expression levels of caspase-3 and caspase-9 were elevated in the treated CAR cells. The Cur-NP-triggered apoptosis was blocked by specific inhibitors of pan-caspase (z-VAD-fmk), caspase-3 (z-DEVD-fmk), caspase-9 (z-LEHD-fmk) and antioxidant agent (N-acetylcysteine; NAC). Cur-NPs increased reactive oxygen species (ROS) production, upregulated the protein expression levels of cleaved caspase-3/caspase-9, cytochrome c, Apaf-1, AIF, Bax and downregulated the protein levels of Bcl-2. Our results suggest that Cur-NPs triggered the intrinsic apoptotic pathway through regulating the function of multiple drug resistance protein 1 (MDR1) and the production of reactive oxygen species (ROS) in CAR cells. Cur-NPs could be potentially efficacious in the treatment of cisplatin-resistant human oral cancer.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Survival; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; Nanoparticles; Reactive Oxygen Species

An in vitro study was carried out to evaluate the effect of curcumin, lycopene, and irradiation upon oral squamous cell carcinoma (OSCC).. Curcumin and lycopene were administrated at doses of 3, 4.25, 5.50, and 6.75 μM in PE/CA-PJ15 OSCC cultures irradiated with different doses (1, 2.5, and 5 Gy), followed by evaluation of the effects upon cell viability, apoptosis, and migration after 24, 48, and 72 h of incubation.. The application of curcumin or lycopene to the tumor cells during 24, 48, and 72 h without irradiation exerted an inhibitor effect upon cell viability and increased cell apoptosis. The maximum reduction in cell viability and the peak apoptotic effect was recorded with the 5.50 and 6.75 μM doses, for both curcumin and lycopene. Likewise, curcumin and lycopene exerted a synergic effect upon both variables on applying irradiation. Lastly, the 5.50 and 6.75 μM drug doses, together with 5 Gy of irradiation, yielded the greatest decrease in cell migration capacity with both curcumin and lycopene.. Curcumin and lycopene increase cytotoxic activity in the PE/CA-PJ15 cell line and reduce cell migration capacity, while the combination of curcumin or lycopene with irradiation exerts a synergic effect.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Carcinoma, Squamous Cell; Carotenoids; Cell Survival; Combined Modality Therapy; Curcumin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Synergism; Humans; Lycopene; Mouth Neoplasms; Time Factors; Tumor Cells, Cultured

Co-culture of periodontal ligament fibroblasts (PDLs) and SCC-25 oral squamous carcinoma cells (OSCC) results in conversion of PDLs into carcinoma-associated fibroblasts (CAFs) and induces epithelial-to mesenchymal transition (EMT) of OSCC tumor cells. We hypothesized that Curcumin targets this dynamic mutual interaction between CAFs and tumor cells. Normal and 2 μM Curcumin-treated co-culture were performed for 4 days, followed by analysis of tumor cell invasivity, mRNA/protein expression of EMT-markers and mediators, activity measure of matrix metalloproteinase 9 (MMP-9), and western blot analysis of signal transduction in tumor cells and fibroblasts. In Curcumin-treated co-culture, in tumor cells, the levels of nuclear factor κB (NFκBα) and early response kinase (ERK)-decreased, in fibroblasts, integrin αv protein synthesis decreased compared to corresponding cells in normal co-culture. The signal modulatory changes induced by Curcumin caused decreased release of EMT-mediators in CAFs and reversal of EMT in tumor cells, which was associated with decreased invasion. These data confirm the palliative potential of Curcumin in clinical application.

Topics: Biomarkers, Tumor; Blotting, Western; Carcinoma, Squamous Cell; Cell Communication; Coculture Techniques; Curcumin; Epithelial-Mesenchymal Transition; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Integrin alphaV; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mouth Neoplasms; Neoplasm Invasiveness; NF-kappa B; Periodontal Ligament; RNA, Messenger; Signal Transduction

There is increasing interest in using natural products as anticancer agents, as many have antioxidative properties that may help to prevent cellular damage that can lead to cancer. In addition, there is the expectation that many natural products will have low toxicity and few side effects. However, most anticancer and antioxidative agents are hydrophobic, reducing their bioavailability in vivo and making them problematic to deliver. Curcumin provides a good model system for study. In low doses it shows both anticancer and antioxidation effects, whereas in high doses and delivered locally it could be cytotoxic for cancer cells. In this paper, curcumin microemulsions were formed with food-grade chemicals, including soybean lecithin, soybean oil, and Tween 80, a Food and Drug Administration-approved surfactant. The optimized composition formed curcumin microemulsions with a mean size of 40-50 nm, carrying a concentration of curcumin as high as 15 μM. The stability of curcumin microemulsions refrigerated at 5°C over at least 968 days was assessed by size distribution and zeta potential. The effects of low-frequency ultrasound on two oral squamous cell carcinoma cell lines (OSCC-4 and OSCC-25), and the synergy between treatment with curcumin microemulsions and low-frequency sonic stimulation, were tested. Finally, microscopic imaging of the cells confirmed the toxic effects of the curcumin microemulsions, showing damaged and ruptured cells after treatment. Brief exposure to the curcumin-containing microemulsions did have cytotoxic effects, but the addition of ultrasound strongly enhanced those effects, especially on OSCC-25 cells.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Curcumin; Delayed-Action Preparations; Drug Carriers; Drug Stability; Emulsions; Humans; Mouth Neoplasms; Nanoparticles; Particle Size; Ultrasonic Therapy; Ultrasonography

Curcumin, a major active component of turmeric Curcuma longa, has been shown to have inhibitory effects on cancers. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effects of curcumin is unclear. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, little data are available regarding the role of autophagy in oral cancers. In this study, we have shown that curcumin has anticancer activity against oral squamous cell carcinoma (OSCC). Induction of autophagy, marked by autophagic vacuoles formation, was detected by acridine orange staining and monodansylcadaverine (MDC) dye after exposure to curcumin. Conversion of LC3-I to LC3-II, a marker of active autophagosome formation, was also detectable by Western blot following curcumin treatment. We have also observed that curcumin induced reactive oxygen species (ROS) production and autophagic vacuoles formation by curcumin was almost completely blocked in the presence of N-acetylcystein (NAC), an antioxidant. Rescue experiments using an autophagy inhibitor suppressed curcumin-induced cell death in OSCC, confirming that autophagy acts as a pro-death signal. Furthermore, curcumin shows anticancer activity against OSCC via both autophagy and apoptosis. These findings suggest that curcumin may potentially contribute to oral cancer treatment and provide useful information for the development of a new therapeutic agent.

Topics: Acetylcysteine; Acridine Orange; Antineoplastic Agents; Apoptosis; Autophagy; Blotting, Western; Cadaverine; Carcinoma, Squamous Cell; Cell Proliferation; Curcumin; Flow Cytometry; Humans; Microtubule-Associated Proteins; Mouth Neoplasms; Reactive Oxygen Species; Staining and Labeling; Tumor Cells, Cultured; Vacuoles

In the present study, post-treatment effects of dietary turmeric on markers related to apoptosis, cell proliferation, and inflammation in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) tumors were investigated. Tumors were induced by applying 0.5% DMBA topically to the HBP three times per week for 12 weeks. After tumor development, half of the animals continued on the control diet and the other half were shifted to a 1% turmeric diet for 4 weeks. To rule out DMBA discontinuation as a cause of inhibition in tumor growth, DMBA treatment was continued during dietary exposure of turmeric in another set of animals until the end of the experiment. The turmeric diet inhibited tumor growth in animals with or without DMBA carcinogen treatment compared to the animals on the control diet. When compared to hamsters bearing tumors that remained on the control diet, the buccal pouches of hamsters bearing tumors receiving turmeric showed the following results: (1) decreased cell proliferation (diminished PCNA, cyclin D1, and Bcl-2) and PCNA labelling index, (2) enhanced apoptosis (increased Bax, caspase-3, caspase-9, and cytochrome c, and decreased survivin) and apoptotic index, (3) decreased inflammation (decreased Cox-2), and (4) decreased MAPK activation (p-ERK and p-p38). These data indicate that tumor growth decreased due to the modulation of cellular pathways associated with cell proliferation and apoptosis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Cell Proliferation; Cheek; Cricetinae; Curcuma; Curcumin; Inflammation; Male; Mesocricetus; Mouth Neoplasms; NF-kappa B; Phytotherapy

An in vitro study was made to evaluate the effect of curcumin and irradiation upon oral squamous cell carcinoma.. Curcumin was administered at doses of 3, 3.75, 4.50 and 5.25 μM in PE/CA-PJ15 oral squamous cell carcinoma cultures irradiated with different doses (1, 2.5 and 5 Gy), followed by evaluation of the effects upon cell viability after 24, 48 and 72 h, based on the MTT colorimetric test.. The application of curcumin to the PECA/PJ15 tumor cells during 24, 48 and 72 h of incubation without irradiation exerted an inhibitor effect upon cell viability. The curcumin concentration at which the inhibition of cell viability proved maximum was 5.25 μM, with statistically significant differences for 24 h (p = 0.002), 48 h (p < 0.001) and 72 h of incubation (p < 0.001). In contrast, the combination of curcumin and irradiation exerted a synergic effect-the greatest effects in relation to cell viability being recorded with a curcumin concentration of 3.75 μM and 5 Gy of irradiation, in the studied cell line.. Curcumin increases cytotoxic activity in the PE/CA PJ15 cell line, while the combination of curcumin and irradiation exerts a synergic effect.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Colorimetry; Coloring Agents; Curcumin; Humans; Mouth Neoplasms; Neoadjuvant Therapy; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tetrazolium Salts; Thiazoles; Time Factors

Curcumin has been reported to inhibit cell growth and induce apoptosis in oral cancer cells. Although many studies have been done to uncover the mechanisms by which curcumin exerts its antitumor activity, the precise molecular mechanisms remain to be unclear. In the present study, we assessed the effects of curcumin on cell viability and apoptosis in oral cancer. For mechanistic studies, we used multiple cellular and molecular approaches such as gene transfection, real-time RT-PCR, Western blotting, invasion assay, and ELISA. For the first time, we found a significant reduction in cell viability in curcumin-treated cells, which was consistent with induction of apoptosis and also associated with down-regulation of Notch-1 and nuclear factor-κB (NF-κB). Taken together, we conclude that the down-regulation of Notch-1 by curcumin could be an effective approach, which will cause down-regulation of NF-κB, resulting in the inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of Notch-1 and NF-κB signaling pathways.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9; Mouth Neoplasms; NF-kappa B; Receptor, Notch1; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Time Factors; Vascular Endothelial Growth Factor A

The purpose of this article is to examine the effect of curcumin on the proliferation and metastasis of human tongue squamous cell carcinoma and analyze its mechanism.. SCC-4 were treated with curcumin of 0, 5, 10, 20, 30, 60, 100 micromol x L(-1) in 24 h. MTT assay, Matrigel invasion assay, flow cytometry and fluorescence microscopy were used to examine the effect of curcumin on the growth and metastasis of SCC-4. cDNA microarray and RT-PCR were employed to analyze the expression of genes treated by curcumin.. The results showed that curcumin could concentration-dependently inhibit SCC-4 cell proliferation at the concentration range from 20 to 100 micromol x L(-1). Furthermore, Matrigel invasion assay indicated that curcumin can reduce SCC-4 cell invasion under the dosage of 20, 30, 60 micromol x L(-1). Flow cytometry also showed that curcumin can influence the distribution of cell cycle of SCC-4 cell with the dosage of 20, 30, 60 micromol x L(-1). And the dosage of 30 micromol x L(-1) curcumin could lead to the recruitment of alpha-tubulin. cDNA microarray showed that 87 genes were activated and 198 genes were inhibited with the effect of curcumin. These results were validated by the real time quantitative RT-PCR.. According to the results, it suggests that curcumin has the potential as the leading compound for anti-cancer proliferation and invasion in oral cancer treatment, and cdc27, EGFR substrate 15, PPAR-alpha and H2A histone may play an important role among this multiple anticancer-targeting ability.

Topics: Cell Line, Tumor; Cell Proliferation; Curcumin; Humans; Mouth Neoplasms

To evaluate the chemopreventive effects of boswellic acid and curcumin on 7,12-dimethyl benzanthracene(DMBA)-induced oral carcinogenesis in the hamster cheek pouch model.. Male Syrian golden hamsters (6 - 8 weeks old, 80 - 130 g in weight) were randomly divided into seven groups, with group A serving as the untreated negative control. The left cheek pouch of the remaining hamsters was topically treated with 0.5% DMBA in mineral oil three times a week for 6 weeks. They were then randomized to six groups with group B serving as a positive control and receiving no further treatment. Groups C-G were treated topically with 5, 10 mg/L boswellic acid, 5, 10 µmol/L curcumin, or the combination of 5 mg/L boswellic acid and 5 µmol/L curcumin three times per week for 18 weeks. The animals were injected with bromodeoxyuridine intraperitoneally at 50 mg/kg 2 h prior to killing. At the 25 th week all the hamsters were sacrificed and cheek pouch tissue was harvested. One half of the tissue was snap frozen in liquid nitrogen for analysis of arachidonic acid metabolites, and the other half was fixed in 10% phosphate-buffered saline(PBS)-buffered formalin for histopathological examination.. Six-weeks of DMBA followed by 18-weeks of topical application of boswellic acid and curcumin, both boswellic acid (5, 10 mg/L) and curcumin (5, 10 µmol/L) significantly inhibited the incidence from 93.8% to 73.9% (P > 0.05), numbers from 2.19 ± 0.98 to 1.13 ± 0.81 (P < 0.01) and size of visible tumors. Microscopically the incidence of squamous cell carcinoma and BrdU index were also significantly suppressed by boswellic acid and curcumin.. Both boswellic acid and curcumin were effective in preventing oral carcinogenesis in DMBA-induced hamster cheek pouch model.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Bromodeoxyuridine; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cricetinae; Curcumin; Hyperplasia; Leukotriene B4; Male; Mesocricetus; Mouth Neoplasms; Precancerous Conditions; Random Allocation; Triterpenes

Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion, so the identification of agents inhibiting the onset and progression of OSCC has recently gained interest. Here, we found that curcumin inhibited cell proliferation and motility with decreased activities of matrix metalloproteinase (MMP)-2/9 and decreased mRNA expressions of urokinase-type plasminogen activator (uPA) and its receptor uPAR in the highly invasive human YD-10B OSCC cells. Western blot analysis showed that curcumin inhibited the activation of MAP kinases (especially ERK) and NF-kappaB, which are involved in the transcriptional regulation of proteolytic enzymes. In conclusion, curcumin is one of the strong phytochemicals with antimotility activity of OSCC; the inhibitory effect of curcumin on the motility of YD-10B cells could result from its potential to inhibit the activation of ERK/MAP kinase and NF-kappaB that consequently down-regulate the mRNA expressions and activities of proteolytic enzymes such as uPA and MMP-2/9.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Migration Assays; Cell Movement; Curcumin; Drug Evaluation, Preclinical; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; NF-kappa B; Phytotherapy; Plant Extracts

Curcumin is a common food ingredient derived from the plant Curcuma longa and is a potent drug against tumorigenesis. Both insulin-like growth factor binding protein-5 (IGFBP-5) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) are suppressors of head and neck carcinogenesis. We identified curcumin as an inducer of IGFBP-5 expression in multiple types of oral keratinocytes; furthermore, curcumin induces IGFBP-5 promoter activity in SAS oral cancer cells. Promoter deletion mapping identified a region (nt -71 to nt -59 relative to the transcription start site) as containing a C/EBPalpha-binding element that is indispensable for curcumin-mediated IGFBP-5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPalpha to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBPalpha expression and IGFBP-5 expression through p38 activation and this was abrogated by SB203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBPalpha, increasing IGFBP-5 promoter activity and expression. Finally, curcumin-induced IGFBP-5 expression is associated with the suppression of xenograft tumorigenesis in mice due to oral cancer cells. We conclude that curcumin activates p38, which, in turn, activates the C/EBPalpha transactivator by interacting with binding elements in the IGFBP-5 promoter. The consequential upregulation of C/EBPalpha and IGFBP-5 by curcumin is crucial to the suppression of oral carcinogenesis.

Topics: Animals; Base Sequence; Blotting, Western; CCAAT-Enhancer-Binding Protein-alpha; Chromatin Immunoprecipitation; Curcumin; DNA Primers; Electrophoretic Mobility Shift Assay; Female; Insulin-Like Growth Factor Binding Protein 5; Mice; Mice, Inbred NOD; Mice, SCID; Mouth Neoplasms; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity; however the treatment approaches are still unsatisfactory. We used a luciferase-transfected animal model to evaluate the therapeutic effects of curcumin. Human oral squamous cell carcinoma SAS cell line was stably transfected with luc gene, named SAS/luc cells. For the in vivo study, they were inoculated subcutaneously to 6-week-old male NOD/SCID mice which were separated into four groups for intraperitoneal injection (i.p.) of curcumin: control, daily with 35 mg/kg, 70 mg/kg every 2 days, and 100 mg/kg every 3 days. We applied SAS/luc bearing animal model and bioluminescent imaging (BLI) to study the inhibition effect of curcumin on tumor growth. The cytotoxic effect of curcumin on SAS/luc cells was mainly at G2/M phase and a significant dose dependent increase of the apoptotic SAS/luc cells as represented by sub-G1 phase was shown. Therapeutic efficacy evaluated by both caliper assay and BLI showed a significant difference between curcumin-treated mice and the controls (p < 0.01). The significant inhibition effects of curcumin on the proliferation and the growth of human OSCC are observed both in vitro and in vivo. No significant body weight change (i.e. within 20%) was observed in all SAS/luc-bearing mice with or without curcumin treatment. This SAS/luc human OSCC bearing animal model combined with multimodalities of molecular imaging permits a sensitive and non-invasive approach to evaluate the therapeutic efficacy in vivo.

Topics: Animals; Antineoplastic Agents; Autoradiography; Carcinoma, Squamous Cell; Cell Cycle; Curcumin; Humans; Luciferases; Luminescence; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mouth Neoplasms; Positron-Emission Tomography; Transplantation, Heterologous

Extensive research within the past half-century has indicated that curcumin (diferuloylmethane), a yellow pigment in curry powder, exhibits anti-oxidant, anti-inflammatory, and pro-apoptotic activities. We investigated whether the anti-pre-cancer activities assigned to curcumin are mediated through an anti-oxidant and DNA-protecting mechanism. Patients with oral leukoplakia, oral submucous fibrosis or lichen planus, and healthy individuals (n = 25 for each group) aged 17-50 years were selected. Salivary and serum oxidative markers such as malonaldehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), vitamins C and E were measured just prior to the intake of curcumin, after one week of curcumin intake and following clinical cure of precancerous lesions. Serum and salivary vitamins C and E showed increases, while MDA and 8-OHdG levels showed decreases in patients with oral leukoplakia, submucous fibrosis and lichen planus after intake of curcumin for all categories of precancerous lesions. The changes in these values were observed to be statistically significant after clinical cure of the disease (P < 0.05). The five-point rating scale for pain, as well as lesion size in oral leukoplakia, submucous fibrosis and lichen planus, improved significantly (P < 0.05). In addition, in submucous fibrosis, mouth opening (P < 0.05) recovered significantly. In oral leukoplakia, submucous fibrosis and lichen planus, the levels of serum and salivary vitamins C and E increased significantly, while MDA and 8-OHdG levels decreased after 131(15), 211(17), and 191(18) days, respectively. Values for serum and salivary vitamins C and E showed a significant decrease in oral leukoplakia, submucous fibrosis and lichen planus, in contrast to healthy individuals, but increased significantly in all groups subsequent to curcumin administration after clinical cure of lesions. Based on these results, we can conclude that curcumin mediates its anti-pre-cancer activities by increasing levels of vitamins C and E, and preventing lipid peroxidation and DNA damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Antioxidants; Ascorbic Acid; Biomarkers; Curcumin; Deoxyguanosine; DNA; DNA Damage; Female; Follow-Up Studies; Free Radical Scavengers; Humans; Leukoplakia, Oral; Lichen Planus, Oral; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Mouth Neoplasms; Oral Submucous Fibrosis; Oxidative Stress; Pain Measurement; Precancerous Conditions; Protective Agents; Saliva; Vitamin E; Young Adult

Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent. Inhibition of the histone acetyltransferase (HAT) activity of p300 by a water-soluble, small molecule inhibitor, Hydrazinocurcumin (CTK7A), substantially reduced the xenografted oral tumor growth in mice. These results, therefore, not only establish an epigenetic target for oral cancer, but also implicate a HAT inhibitor (HATi) as a potential therapeutic molecule.

Topics: Acetylation; Animals; Cell Proliferation; Cellular Senescence; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenases; HeLa Cells; Histone Acetyltransferases; Histones; Humans; Hydrazines; Mice; Mice, Nude; Mouth Neoplasms; Nitric Oxide; Nuclear Proteins; Nucleophosmin; p300-CBP Transcription Factors; Solubility; Up-Regulation; Water

Hypoxia inducible factor (HIF)-1α gene expression is mainly induced by tissue hypoxia. Overexpression of HIF-1α has been demonstrated in a variety of cancers. The aim of this study was to compare HIF-1α expression in normal human oral epithelium and areca quid chewing-associated oral squamous cell carcinoma (OSCC) and further to explore the potential mechanisms that may lead to induce HIF-1α expression.. Twenty-five OSCC from areca quid chewing-associated OSCC and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms.. Hypoxia inducible factor-1α expression was significantly higher in OSCC specimens than normal specimen (P<0.05). Arecoline was found to elevate HIF-1α expression in a dose- and time-dependent manner (P<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HIF-1α expression (P<0.05).. Hypoxia inducible factor-1α expression is significantly upregulated in areca quid chewing-associated OSCC and HIF-1α expression induced by arecoline is downregulated by NAC, curcumin, PD98059, and staurosporine.

Topics: Acetylcysteine; Areca; Arecoline; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma, Squamous Cell; Cell Line; Cholinergic Agonists; Curcumin; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Free Radical Scavengers; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Mouth Mucosa; Mouth Neoplasms; Protein Kinase C; Staurosporine; Time Factors; Transcription Factor AP-1

The modulating effect of curcumin and ferulic acid was investigated on expression pattern of apoptosis regulatory p53 and bcl-2 proteins in oral squamous cell carcinoma (OSCC). The OSCC was induced in the buccal pouch of golden Syrian hamster by painting with 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) three-times a week for 14 weeks. The expression pattern of p53 and bcl-2 proteins was analyzed by immunohistochemical staining. We noticed 100% tumor formation in hamsters painted with DMBA alone for 14 weeks. Overexpression of p53 and bcl-2 proteins was observed in the buccal mucosa of tumor-bearing hamsters. Oral administration of curcumin (80 mg/kg body wt) and ferulic acid (40 mg/kg body wt) to DMBA painted hamsters on days alternate to DMBA painting for 14 weeks completely inhibited tumor formation and down-regulated the expression pattern of p53 and bcl-2 proteins. Our results thus demonstrated the protective role of curcumin and ferulic acid on DMBA-induced abnormal expression of p53 and bcl-2 proteins in the buccal mucosa of golden Syrian hamsters.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Coumaric Acids; Cricetinae; Curcumin; Immunohistochemistry; Male; Mesocricetus; Mouth Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Oral carcinoma accounts for 40-50 percent of all cancers in India. Tobacco chewing, smoking and alcohol consumption are the major risk factors associated with the high incidence of oral cancer in India. Our aim was to investigate the chemopreventive potential of curcumin and piperine during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis.. Oral squamous cell carcinoma was developed in the buccal pouch of Syrian golden hamsters, by painting them with 0.5 percent DMBA in liquid paraffin, three times a week for 14 weeks. The tumour incidence, tumour volume and burden were determined in the buccal pouches. The status of phase II detoxification agents, lipid peroxidation and antioxidants were estimated by specific colorimetric methods.. We observed 100 percent tumour formation in DMBA-alone painted hamsters. Disturbances in the status of lipid peroxidation, antioxidants and phase II detoxification agents were noticed in DMBA-alone painted hamsters. Oral administration of curcumin (80 mg/kg body weight) and piperine (50 mg/kg body weight) to DMBA-painted hamsters on alternate days to DMBA painting for 14 weeks completely prevented the formation of oral carcinoma. Also, curcumin and piperine restored the status of lipid peroxidation, antioxidants and detoxifying agents in DMBA-painted hamsters.. The chemopreventive efficacy of curcumin and piperine is probably due to their antilipidperoxidative and antioxidant potential as well as their modulating effect on the carcinogen detoxification process.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkaloids; Animals; Anticarcinogenic Agents; Antioxidants; Benzodioxoles; Carcinogens; Carcinoma, Squamous Cell; Cheek; Colorimetry; Cricetinae; Curcumin; Humans; Lipid Peroxidation; Mesocricetus; Mouth Neoplasms; Piperidines; Polyunsaturated Alkamides

Heat shock protein 70 (HSP70) is an important stress-induced protein. Areca quid chewing is a major risk factor of oral squamous cell carcinoma (OSCC). The aim of this study was to compare HSP70 expression in normal human oral epithelium and OSCC and further to explore the potential mechanisms that may lead to induce HSP70 expression. 41 OSCC and 10 normal epithelium specimens were examined by immunohistochemistry and analyzed by the clinico-pathological profiles. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms. The results from immunohistochemistry demonstrated that HSP70 expression was significantly higher in OSCC specimens (p<0.05). No significant difference in HSP70 expression was observed with respect to age, sex, T category, and stage (p>0.05). The low HSP70 expression was associated with lymph node metastasis (p=0.005). The high HSP70 expression was found in poor differentiated tumor groups (p=0.036). Arecoline was found to elevate HSP70 expression in a dose- and time-dependent manner (p<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HSP70 expression (p<0.05). Taken together, HSP70 expression is significantly upregulated in areca quid chewing-associated OSCC. HSP70 could be used clinically as a marker for tumors possessing the potential for differentiation as well as lymph node metastasis. In addition, arecoline-induced HSP70 expression was downregulated by NAC, curcumin, PD98059, and staurosporine.

Topics: Adult; Aged; Antineoplastic Agents; Areca; Arecoline; Blotting, Western; Carcinoma, Squamous Cell; Curcumin; Epithelium; Female; Flavonoids; HSP70 Heat-Shock Proteins; Humans; Lymphatic Metastasis; Male; Mastication; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Staurosporine; Up-Regulation

The chemopreventive efficacy of turmeric has been established in experimental systems. However, its mechanism(s) of action are not fully elucidated in vivo. The present study investigates the mechanism of turmeric-mediated chemoprevention in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis at 2, 4, 6, 10 and 12 weeks. Dietary turmeric (1%) led to decrease in DMBA-induced tumor burden and multiplicity, and enhanced the latency period in parallel, to its modulatory effects on oncogene products and various cellular responses during HBP tumorigenesis. DMBA-induced expression of ras oncogene product, p21 and downstream target, the mitogen-activated protein kinases were significantly decreased by turmeric during HBP carcinogenesis. Turmeric also diminished the DMBA-induced mRNA expression of proto-oncogenes (c-jun, c-fos) and NF-kappaB, leading to decreased protein levels and in further attenuation of DMBA-induced AP-1/NF-kappaB DNA-binding in the buccal pouch nuclear extracts. Besides, buccal pouch of hamsters receiving turmeric diet showed significant alterations in DMBA-induced effects: (a) decrease in cell proliferation (diminished PCNA and Bcl2 expression), (b) enhanced apoptosis (increased expression of Bax, caspase-3 and apoptotic index), (c) decrease in inflammation (levels of Cox-2, the downstream target of AP-1/NF-kappaB, and PGE2) and (d) aberrant expression of differentiation markers, the cytokeratins (1, 5, 8, and 18). Together, the protective effects of dietary turmeric converge on augmenting apoptosis of the initiated cells and decreasing cell proliferation in DMBA-treated animals, which in turn, is reflected in decreased tumor burden, multiplicity and enhanced latency period. Some of these biomarkers are likely to be helpful in monitoring clinical trials and evaluating drug effect measurements.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Cell Proliferation; Cheek; Cricetinae; Curcuma; Diet; Keratins; Male; MAP Kinase Signaling System; Mesocricetus; Mouth Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras); Transcription Factor AP-1

Smokeless tobacco (ST) consumption is a major cause of oral cancer in South East Asia including India. Recently, we showed that exposure to smokeless tobacco extract (STE) (khaini) results in increased expression and activation of nuclear factor-kappaB (NF-kappaB) and its downstream target cyclooxygenase-2 (COX-2) in human oral cell systems in vitro. The present study was designed to test the hypothesis that curcumin may inhibit the activation of NF-kappaB in ST exposed oral premalignant and cancer cells. Exposure of oral premalignant and cancer cells to curcumin resulted in significant decrease in cell viability and induced apoptosis. STE-induced nuclear translocation and DNA-binding activity of NF-kappaB were inhibited in curcumin pretreated oral premalignant and cancer cells in vitro. Curcumin treatment led to decreased expression of NF-kappaB and COX-2. The tobacco specific nitrosamine, 4-(methylnitrosamino-)-1-(3-pyridyl)-1-butanone (NNK), is one of the carcinogenic components of STE (khaini). We demonstrate that curcumin pretreatment abrogated NNK-induced activation of NF-kappaB and COX-2 expression, suggesting that NNK is one of the factors in STE (khaini) modulated by curcumin. In conclusion, our findings demonstrate for the first time that curcumin downregulates STE (khaini) or NNK-induced NF-kappaB and COX-2 in oral premalignant and cancer cells in vitro.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Curcumin; Cyclooxygenase 2; Down-Regulation; Humans; Mouth Neoplasms; NF-kappa B; Precancerous Conditions; Tobacco, Smokeless; Tumor Cells, Cultured

Curcumin, a potential chemopreventive agent, was found to inhibit cancer cells in S/G2M phases of the cell cycle, when radiation is more effective. The purpose of the current study was to investigate whether curcumin can sensitize squamous cell carcinoma (SCC) cells to the ionizing effects of irradiation.. Curcumin (3.5 microM) was added for 48 hours to an SCC cell line prior to irradiation. Cell growth (counts) and colony-formation (colonogenic assay) were examined after radiation.. Incubation with curcumin only (3.75 microM) for 48 hours did not decrease the number of cells or the ability to form colonies in the absence of radiation. However, in plates that were exposed to 1-5 Gy of radiation, cell counts dropped significantly if pretreated with curcumin with a maximal effect at 2.5 Gy (where the cell counts dropped from 1240 to 1017, P < 0.001). The colonogenic assay revealed a significant decrease in the ability to form colonies following pretreatment with curcumin in all radiation doses ( P < 0.05).. Given the appropriate doses, curcumin exhibits radio-sensitizing effects on SCC cells in vitro.

Topics: Carcinoma, Squamous Cell; Cell Count; Cell Culture Techniques; Cell Line, Tumor; Curcumin; G2 Phase; Humans; Mouth Neoplasms; Radiation-Sensitizing Agents; S Phase; Tumor Stem Cell Assay

Tea is one of the most popular beverages consumed in the world. Curcumin, the major yellow pigment in turmeric, is used widely as a spice and food-coloring agent. In this study, we studied the effects of tea and curcumin on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamsters. DMBA solution (0.5% in mineral oil, 0.1 ml) was applied topically to the left cheek pouch of male Syrian golden hamsters 3 times/week for 6 weeks. Two days after the last treatment of DMBA, the animals received green tea (6 mg tea solids/ml) as drinking fluid, or 10 mmol curcumin applied topically 3 times/week, or the combination of green tea and curcumin treatment, or no treatment for 18 weeks. The combination of tea and curcumin significantly decreased the oral visible tumor incidence from 92.3% (24/26) to 69.2% (18/26) and the squamous cell carcinoma (SCC) incidence from 76.9% (20/26) to 42.3% (11/26). The combination of tea and curcumin also decreased the number of visible tumors and the tumor volume by 52.4 and 69.8%, as well as the numbers of SCC, dysplasic lesions and papillomas by 62.0, 37.5 and 48.7%, respectively. Green tea or curcumin treatment decreased the number of visible tumors by 35.1 or 39.6%, the tumor volume by 41.6 or 61.3% and the number of SCC by 53.3 or 51.3%, respectively. Green tea also decreased the number of dysplasic lesions. Curcumin also significantly decreased the SCC incidence. Tea and curcumin, singly or in combination, decreased the proliferation index in hyperplasia, dysplasia and papillomas. Only the combination treatment decreased the proliferation index in SCC. Tea alone and in combination with curcumin significantly increased the apoptotic index in dysplasia and SCC. Curcumin, alone and in combination with tea, significantly inhibited the angiogenesis in papilloma and SCC. The results suggested that green tea and curcumin had inhibitory effects against oral carcinogenesis at the post-initiation stage and such inhibition may be related to the suppression of cell proliferation, induction of apoptosis and inhibition of angiogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Apoptosis; Carcinogens; Cell Division; Cricetinae; Curcumin; Male; Mesocricetus; Mouth Neoplasms; Neovascularization, Pathologic; Tea

The development of oral squamous cell carcinoma (SCC) shows a positive correlation with the carcinogen exposure that occurs during tobacco and alcohol use. The purpose of this study was to investigate whether the naturally occurring chemopreventive agent, curcumin, modulates expression and function of carcinogen- metabolizing enzymes in human keratinocytes isolated from oral SCC tumors. Dose-response studies demonstrated that curcumin concentrations of >or=25 micro M were cytotoxic for oral SCC cells. Curcumin increased both expression (reverse transcription-PCR analyses) and function (high-performance liquid chromatography determination of ethoxyresorufin metabolism) of cytochrome P-450 (CYP) 1A1 and/or CYP1B1. The aryl hydrocarbon receptor (AhR), which up-regulates a battery of genes associated with carcinogen metabolism, is activated by polycyclic aromatic hydrocarbons such as the tobacco-associated carcinogen benzo(a)pyrene. Electromobility shift assays demonstrated that similar to the established AhR ligand 2,3,7,8,-tetrachlorodibenzo-p-dioxin, curcumin inclusion resulted in AhR nuclear translocation and formation of the transcriptionally active AhR-aryl hydrocarbon receptor nuclear translocator complex. Cellular capacity to bioactivate the tobacco-associated carcinogen (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiodiol was determined by evaluating conversion of the carcinogenic metabolite diol epoxide to stable tetrols via high-performance liquid chromatography. Results of our metabolism studies showed that curcumin significantly inhibited CYP1A1-mediated benzo(a)pyrene diol bioactivation in both oral SCC cells and intact oral mucosa. Because CYP1A1 is one of the primary carcinogen-activating enzymes in oral mucosa, the use of curcumin as an oral cavity chemopreventive agent could have significant clinical impact via its ability to inhibit carcinogen bioactivation.

Topics: Adult; Aged; Antineoplastic Agents; Aryl Hydrocarbon Hydroxylases; Aryl Hydrocarbon Receptor Nuclear Translocator; Biotransformation; Carcinogens; Carcinoma, Squamous Cell; Cell Division; Cell Survival; Curcumin; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Dihydroxydihydrobenzopyrenes; DNA-Binding Proteins; Glutathione; Humans; Keratinocytes; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Oxazines; Receptors, Aryl Hydrocarbon; Transcription Factors; Tumor Cells, Cultured

0.5% DMBA solution (in mineral oil) was applied topically to the left cheek pouch of male Syrian golden hamsters 3 times per week for 6 weeks. After the last treatment of DMBA, the animals received 0.6% green tea powder as drinking fluid, or 10 mumol curcumin applied topically 3 times per week, or the combination of green tea and curcumin treatment, or no treatment for 18 weeks. The combination of tea and curcumin significantly decreased the oral visible tumor incidence and the squamous cell carcinoma (SCC) incidence. The combination of tea and curcumin also decreased the number of visible tumors and the tumor volume as well as the numbers of SCC, dysplasic lesions, and papillomas respectively. Green tea or curcumin treatment decreased the number of visible tumor, the tumor volume and the number of SCC respectively. Green tea also decreased the number of dysplasic lesions. Curcumin also significantly decreased the SCC incidence. Tea and curcumin, singly or in combination decreased bromodeoxyuridine (BrdU)-labeling index in hyperplasia, dysplasia, and papillomas. Tea alone and in combination with curcumin significantly increased the apoptotic index in dysplasia and SCC. Curcumin alone and in combination with tea inhibited the angiogenesis in papilloma and SCC. The results suggested that green tea and curcumin had inhibitory effects against oral carcinogenesis at the post-initiation stage and such inhibition may be related to the suppression of cell proliferation, induction of apoptosis, and inhibition of angiogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cricetinae; Curcumin; Male; Mesocricetus; Mouth Neoplasms; Plant Extracts; Random Allocation; Tea

An in vitro model for oral cancer was used to examine the growth inhibitory effects of chemopreventive agents when used singly and in combination. The model consists of primary cultures of normal oral epithelial cells, newly established cell lines derived from dysplastic leukoplakia and squamous cell carcinoma. Two naturally occurring substances, (-)-epigallocatechin-3-gallate (EGCG) from green tea and curcumin from the spice turmeric were tested. Cells were treated singly and in combination and effects on growth determined in 5-day growth assays and by cell cycle analysis. Effective dose 50s and the combination index were calculated with the computerized Chou-Talalay method which is based on the median-effect principle. Agents were shown to differ in their inhibitory potency. EGCG was less effective with cell progression; the cancer cells were more resistant than normal or dysplastic cells. In contrast, curcumin was equally effective regardless of the cell type tested. Cell cycle analysis indicated that EGCG blocked cells in G1, whereas curcumin blocked cells in S/G2M. The combination of both agents showed synergistic interactions in growth inhibition and increased sigmoidicity (steepness) of the dose-effect curves, a response that was dose and cell type dependent. Combinations allowed for a dose reduction of 4.4-8.5-fold for EGCG and 2.2-2.8-fold for curcumin at ED50s as indicated by the dose reduction index (DRI). Even greater DRI values were observed above ED50 levels. Our results demonstrate that this model which includes normal, premalignant and malignant oral cells can be used to analyse the relative potential of various chemopreventive agents. Two such naturally-occurring agents, EGCG and curcumin, were noted to inhibit growth by different mechanisms, a factor which may account for their demonstrable interactive synergistic effect.

Topics: Anticarcinogenic Agents; Catechin; Cells, Cultured; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; Epithelial Cells; Flow Cytometry; Humans; Mouth Neoplasms; Precancerous Conditions; Tea

Turmeric and its active principle curcumin have been extensively investigated for their antimutagenic and antioxidant effects in bacterial and animal systems. Because oral cancers are common in India, an experimental model of 7,12-dimethylbenzanthracene-induced buccal pouch tumors in Syrian Golden hamsters was used to evaluate the tumor retardation effects of turmeric and curcumin. Turmeric and/or curcumin was administered in the diet and/or applied locally for 14 weeks along with 7,12-dimethylbenzanthracene. After the experimental period, the animals were sacrificed and oral pouches were examined for tumor number and size. DNA adducts were estimated by 32P postlabel assay in the cheek pouches. Neoplastic changes were graded by histopathology. The results of the study suggest that turmeric or curcumin in the diet and/or applied locally significantly reduced DNA adducts at the target site. Tumor number and tumor burden were significantly lower (p < 0.05) in the animals that received turmeric in the diet and applied locally. The histopathological examinations suggested that the neoplastic grading was least in the animals fed or painted with curcumin (p < 0.05). The current study demonstrates that turmeric or curcumin administered in the diet or applied as paint may have a plausible chemopreventive effect on oral precancerous lesions.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Antioxidants; Cheek; Cricetinae; Curcuma; Curcumin; Diet; DNA Adducts; Mesocricetus; Mouth Neoplasms; Plant Extracts

In vitro studies on the effect of alcoholic extracts of turmeric (TE), turmeric oil (TO) and turmeric oleoresin (TOR), on the incidence of micronuclei (Mn) in lymphocytes from normal healthy subjects showed that the test compounds did not cause any increase in the number of Mn as compared with those found in untreated controls. Further it was observed that all three compounds offered protection against benzo[a]pyrene induced increase in Mn in circulating lymphocytes. In subsequent studies, patients suffering from submucous fibrosis were given a total oral dose of TO (600 mg TO mixed with 3 g TE/day). TOR (600 mg + 3 g TE/day) and 3 g TE/day as a control for 3 months. It was observed that all three treatment modalities decreased the number of micronucleated cells both in exfoliated oral mucosal cells and in circulating lymphocytes. TOR was found to be more effective in reducing the number of Mn in oral mucosal cells (P < 0.001), but in circulating lymphocytes the decrease in Mn was comparable in all three groups.

Topics: Adolescent; Adult; Curcuma; DNA Damage; Humans; Male; Micronuclei, Chromosome-Defective; Mouth Neoplasms; Plant Extracts; Precancerous Conditions

Catechin and dietary turmeric (Curcuma longa) were used as chemopreventive agents in benzo[a]pyrene induced forestomach tumors in Swiss mice and methyl-(acetoxymethyl)-nitrosamine induced oral mucosal tumors in Syrian golden hamsters. Catechin in drinking water and dietary turmeric significantly inhibited the tumor burden and tumor incidence in both tumor models. The induction of oral tumors in golden hamsters was delayed by catechin and dietary turmeric. Adjuvant chemoprevention utilising both catechin and dietary turmeric inhibited both the gross tumor yield and burden more effectively than when compared to individual components in both tumor models. A single i.p. injection of catechin to male Swiss mice induced increased forestomach and hepatic glutathione S-transferase (GST) activity when compared to controls. These findings suggest that catechin and turmeric which are regularly consumed natural products, are effective in mice or golden hamsters as chemopreventive agents.

Topics: Adjuvants, Pharmaceutic; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Catechin; Cricetinae; Curcumin; Diet; Dimethylnitrosamine; Female; Glutathione Transferase; Liver; Male; Mesocricetus; Mice; Mouth Neoplasms; Neoplasms, Experimental; Stomach Neoplasms

The modifying effects of two natural products, curcumin and hesperidin, given during the initiation and postinitiation phases of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats and compared with that of beta-carotene. At 6 weeks of age, rats were divided into experimental and control groups and fed the diet containing beta-carotene, hesperidin, or curcumin at a dose of 0.5 g/kg diet (500 ppm). At 7 weeks of age, all animals except those treated with each test chemical alone and control groups were given 4-NQO (20 ppm) in the drinking water for 8 weeks to induce oral cancer. Seven days after the 4-NQO exposure, groups of animals fed the diets containing test chemicals were switched to the basal diet and continued on this diet until the end of the study. Starting 1 week after the stop of 4-NQO exposure, the groups given 4-NQO and a basal diet were switched to the diets containing beta-carotene, hesperidin, and curcumin and maintained on these diets for 22 weeks. The other groups consisted of rats given 500 ppm beta-carotene, hesperidin, or curcumin alone or untreated rats. All animals were necropsied at the termination of the experiment (week 32). The incidences of tongue neoplasms and preneoplastic lesions, polyamine levels in the tongue tissue, and cell proliferation activity estimated by bromodeoxyuridine-labeling index and by morphometric analysis of silver-stained nucleolar organizer region proteins were compared among the groups. Feeding of curcumin and beta-carotene during the initiation and postinitiation phases and hesperidin at the initiation stage caused a significant reduction in the frequency of tongue carcinoma (41-91% reduction, P < 0.05) and the order of chemopreventive efficacy was curcumin > beta-carotene > hesperidin. The incidences of oral preneoplasia in rats fed the diets mixed with these compounds were also decreased (P < 0.05). There were no such lesions in rats treated with test compounds alone or those in an untreated control group. Dietary administration of these compounds significantly decreased the labeling index of bromodeoxyuridine and the number and area of silver-stained nucleolar organizer region proteins per cell nucleus that are proliferation biomarkers, of the tongue squamous epithelium (P < 0.05). In addition, polyamine levels in the oral mucosa were lowered in rats treated with 4-NQO and three test compounds when compared to those give 4-NQO alone (P < 0.05).(ABST

Topics: 4-Hydroxyaminoquinoline-1-oxide; 4-Nitroquinoline-1-oxide; Animals; beta Carotene; Carcinoma, Squamous Cell; Carotenoids; Curcumin; Hesperidin; Male; Mouth Neoplasms; Nucleolus Organizer Region; Polyamines; Precancerous Conditions; Rats; Rats, Inbred F344; Tongue; Tongue Neoplasms

The inhibitory effect of oral administration of betel-leaf extract (BLE) and 2 of its constituents, beta-carotene and alpha-tocopherol, as single agents or in combination with dietary turmeric on methyl(acetoxymethyl)nitrosamine (DMN-OAC)-induced oral carcinogenesis in Syrian hamsters was studied. DMN-OAC was administered twice monthly for 6 months. The chemopreventive effect of BLE or its constituents with turmeric was determined by comparing tumor incidence observed in treated groups with that seen in control animals. The apparent site-specific chemopreventive effect of BLE or its constituents was demonstrated by inhibition of tumor incidence, reduction of tumor burden, extension of the tumor latency period and regression of established, frank tumors. The inhibitory effect of BLE or its constituents combined with turmeric was higher than that of the individual constituents. The study suggests that BLE could be developed as a potential chemopreventive agent for human oral cancer.

Topics: Animals; Areca; beta Carotene; Carcinogens; Carotenoids; Cricetinae; Curcuma; Dimethylnitrosamine; Drug Screening Assays, Antitumor; Drug Therapy, Combination; Female; Mesocricetus; Mouth Neoplasms; Plant Extracts; Plants, Medicinal; Vitamin E

An ethanol extract of turmeric ("Curcuma longa") as well as an ointment of curcumin (its active ingredient) were found to produce remarkable symptomatic relief in patients with external cancerous lesions. Reduction in smell were noted in 90% of the cases and reduction in itching in almost all cases. Dry lesions were observed in 70% of the cases, and a small number of patients (10%) had a reduction in lesion size and pain. In many patients the effect continued for several months. An adverse reaction was noticed in only one of the 62 patients evaluated.

Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Catechols; Curcuma; Curcumin; Drug Evaluation; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Odorants; Palliative Care; Plant Extracts; Pruritus; Skin Neoplasms; Skin Ulcer; Vulvar Neoplasms