curcumin and Head-and-Neck-Neoplasms

Head and neck squamous cell carcinoma (HNSCC) is one of the most life-threatening diseases which also causes economic burden worldwide. To overcome the limitations of traditional therapies, investigation into alternative adjuvant treatments is crucial.. Curcumin, a turmeric-derived compound, demonstrates significant therapeutic potential in diverse diseases, including cancer. Furthermore, research focuses on curcumin analogues and novel drug delivery systems, offering approaches for improved efficacy. This review aims to provide a comprehensive overview of curcumin's current findings, emphasizing its mechanisms of anti-HNSCC effects and potential for clinical application.. An electronic search of Web of Science, MEDLINE, and Embase was conducted to identify literature about the application of curcumin or analogues in HNSCC. Titles and abstracts were screened to identify potentially eligible studies. Full-text articles will be obtained and independently evaluated by two authors to make the decision of inclusion in the review.. Curcumin's clinical application is hindered by poor bioavailability, prompting the exploration of methods to enhance it, such as curcumin analogues and novel drug delivery systems. Curcumin could exhibit anti-cancer effects by targeting cancer cells and modulating the tumor microenvironment in HNSCC. Mechanisms of action include cell cycle arrest, apoptosis promotion, reactive oxygen species induction, endoplasmic reticulum stress, inhibition of epithelial-mesenchymal transition, attenuation of extracellular matrix degradation, and modulation of tumor metabolism in HNSCC cells. Curcumin also targets various components of the tumor microenvironment, including cancer-associated fibroblasts, innate and adaptive immunity, and lymphovascular niches. Furthermore, curcumin enhances the anti-cancer effects of other drugs as adjunctive therapy. Two clinical trials report its potential clinical applications in treating HNSCC.. Curcumin has demonstrated therapeutic potential in HNSCC through in vitro and in vivo studies. Its effectiveness is attributed to its ability to modulate cancer cells and interact with the intricate tumor microenvironment. The development of curcumin analogues and novel drug delivery systems has shown promise in improving its bioavailability, thereby expanding its clinical applications. Further research and exploration in this area hold great potential for harnessing the full therapeutic benefits of curcumin in HNSCC treatment.

Topics: Antineoplastic Agents; Curcumin; Drug Delivery Systems; Head and Neck Neoplasms; Humans; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

To evaluate the effectiveness of antioxidants in the prevention and management of oral mucositis in adults undergoing radiotherapy and/or chemotherapy with diagnosed head and neck cancer (HNC) compared to placebo intervention.. Cochrane, EMBASE, PubMed, and Web of Science databases were used to search for randomized controlled trials (RCTs) comparing oral or topical antioxidants with placebo in clinically diagnosed HNC adult patients receiving radiotherapy with/without chemotherapy. The primary outcome was to assess the efficacy of the antioxidant to prevent and decrease the incidence/prevalence and severity of oral/oropharyngeal mucositis. The risk of bias was assessed following Cochrane's guidelines.. The database search resulted in 203 records up to February 19, 2021. Thirteen RCTs were included with 650 HNC-diagnosed patients. Included studies showed a statistically significant improvement in mucositis severity score for all antioxidants except melatonin. However, further studies are needed as only one study reported outcomes for zinc, propolis, curcumin, and silymarin. Patients receiving vitamin E were 60% less likely to develop severe mucositis grade 2 or higher than those receiving placebo in one study (P = 0.040). Patients receiving zinc were 95% less likely to develop severe mucositis (grades 3-4) in one study compared to placebo (P = 0.031). One meta-analysis showed no statistical difference in the risk of having severe mucositis (grades 3-4) with 199 patients compared to placebo for honey (n = 2 studies, P = 0.403). Meta-analyses could not be conducted for zinc, propolis, curcumin, melatonin, silymarin, and selenium due to the lack of studies reporting similar outcomes for the same intervention.. Though oral and topical antioxidants significantly improved mucositis severity scores in HNC patients receiving radiotherapy with/without chemotherapy in individual studies, the quality of the evidence was low due to the small number of studies and unclear/high-risk bias. Additionally, large RCTs are needed to confirm these results.

Topics: Adult; Antioxidants; Curcumin; Head and Neck Neoplasms; Humans; Melatonin; Mucositis; Propolis; Silymarin; Stomatitis; Zinc

Neoplastic diseases of the upper respiratory airways, as well as head and neck cancers, are a frequent cause of death and significantly affect the quality of life of both patients and survivors. As the frequency increases, new and improved treatment techniques are sought. Promising properties in this respect are expressed by a natural compound - curcumin. Along with its derivatives, it was found useful in the treatment of a series of cancers. Curcumin was found to be effective in clinical trials and in vitro, in vivo anticancer experiments. Nanoformulations (e.g., poly(lactide-co-glycolic acid)-based nanoparticles, nanoemulsions), and modifications of curcumin, as well as its combinations with other substances (e.g., catechins, cisplatin) or treatments (e.g., radiotherapy or local use in inhalation), were found to enhance the antitumor effect. This review aims to summarize the recent findings for the treatment of head and neck diseases, especially squamous cell carcinomas (HNSCCs), including drawing attention to the constant use of the misidentified Hep-2 cell line and proposing databases purposed at eliminating this problem. Moreover, this manuscript focuses on pointing out the molecular mechanisms of therapy that have been reached and emphasizing the shortcomings that still need to be addressed.

Topics: Antineoplastic Agents; Cell Line, Tumor; Curcumin; Head and Neck Neoplasms; Humans; Quality of Life

Clinical trials have explored the role of curcumin in the prevention and treatment of oral mucositis (OM) in head and neck cancer patients. To provide evidence for curcumin management of OM for clinicians, a comprehensive meta-analysis of these findings is necessary. This meta-analysis aimed to evaluate the efficacy and safety of curcumin for OM caused by radiotherapy (RT) and/or chemotherapy (CT) for head and neck cancer.. Randomized controlled trials were identified from the PubMed, Embase, Web of Science, Cochrane Library, Medline, and Google Scholar databases. RevMan 5.3 was used for statistical analysis to calculate the combined risk ratios (RRs).. Six studies involving 266 patients were included. Curcumin considerably reduced weight loss (mean difference [MD] - 0.78) in both the prophylactic and therapeutic phases. When used as a preventative treatment, curcumin did not reduce the incidence of OM (RR 0.99), but it did reduce the incidence of severe OM (RR 0.44) and the mean severity of OM (SMD -1.44). Curcumin also reduced the severity of OM (MD 0.82) compared to chlorhexidine.. Curcumin is a safe, natural bioactive substance that can effectively prevent and treat OM in patients receiving RT and/or CT, as well as reduce weight loss.

Topics: Curcumin; Databases, Factual; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic; Stomatitis

Oral Mucositis(OM) is an acute debilitating dose limiting toxicity of Radiotherapy/Radiochemotherapy(RT/RCT) in management of Head and Neck Cancer (HNC). Curcumin/Turmeric may reduce OM in patients.. Efficacy of Curcumin/Turmeric for preventing and ameliorating the onset and severity of RT/RCT induced OM was analysed in this review.. A systematic literature search with meta-analysis were performed using Mesh terms in PubMed, Google scholar, Science Direct, Cochrane library and manual searching, articles published from 2010 to April 2021 were included. Clinical trials that studied the efficacy/effects of turmeric / curcumin in management of RT/RCT induced OM in HNC patients were included. Statistical Analysis were done to calculate the pooled Risk ratio at 95%confidence interval with significance at p.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemoradiotherapy; Curcumin; Head and Neck Neoplasms; Humans; Stomatitis

Head and neck squamous cell carcinoma (HNSCC) contributes globally to a great number of deaths and morbidity, in spite of new therapeutic strategies. There is a great need of new drugs that are significantly effective and less deleterious to the patients' general health. In this sense, phytotherapy is a tendency, with results pointing to its use as a chemo-preventive and adjuvant therapy. Therefore, the objective of this systematic review was to investigate the effects of curcumin on proliferation and survival of HNSCC.. The search was conducted on six databases: Cochrane, LILACS, EMBASE, MEDLINE, PubMed, and Web of Science. In vitro and in vivo studies that evaluated the effects of curcumin on cell viability, tumor growth, cell cycle and/or cell death pattern in HNSCC cell lines or animal models were selected.. This systematic review demonstrated that curcumin is effective on HNSCC cell proliferation and survival, reinforcing the currently available evidence that curcumin could be an adjuvant drug in HNSCC treatment.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Survival; Chemotherapy, Adjuvant; Curcumin; Head and Neck Neoplasms; Humans; Squamous Cell Carcinoma of Head and Neck

Head and neck cancer is the sixth large type of cancer in the world. The treatment regimens for head and neck cancer encompass surgery, radiotherapy and chemotherapy. However, all current treatment regimens for head and neck cancer have adverse effects. Therefore, continuing investigations have been undertaken to seek less toxic therapies to reduce treatment morbidity for head and neck cancer. Substantial evidence has demonstrated that curcumin inhibited proliferation, migration, invasion and metastasis and induced apoptosis via modulating multiple signaling pathways in head and neck cancer. Curcumin also suppressed the growth of xenograft derived from head and neck cancer in vivo in animal models. This review summarizes the evidence demonstrating potential use of curcumin as a single chemotherapeutic agent or in combination with other chemotherapeutic agents and radiation to minimize their toxicity in head and neck cancer. Although curcumin has been shown to be safe at doses of 8 g/d in both phase I and phase II clinical trials, its bioavailability is poor. Overcoming the poor bioavailability of curcumin in the near future would facilitate its clinical use.

Topics: Animals; Antineoplastic Agents; Curcumin; Head; Head and Neck Neoplasms; Humans; Neck; Signal Transduction

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

Topics: Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Carcinoma, Squamous Cell; Curcumin; Head and Neck Neoplasms; Humans

Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers worldwide. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development, which underscore the importance of novel strategies for cancer prevention. Cancer chemoprevention, the use of natural or synthetic compounds to prevent, arrest, or reverse the process of carcinogenesis at its earliest stages, aims to reverse premalignancies and prevent second primary tumors. Genomics and proteomics information including initial mutation, cancer promotion, progression, and susceptibility has brought molecularly targeted therapies for drug development. The development of preventive approaches using specific natural or synthetic compounds, or both, requires a depth of understanding of the cross-talk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Many natural dietary compounds have been identified with multiple molecular targets, effective in the prevention and treatment of cancer. This review describes recent advances in the understanding of the complex signaling networks driving cancer progression and of molecularly targeted natural compounds under preclinical and clinical investigation.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Catechin; Curcumin; Cyclooxygenase 2 Inhibitors; ErbB Receptors; Head and Neck Neoplasms; Humans; NF-kappa B; Resveratrol; Stilbenes; TOR Serine-Threonine Kinases; Tumor Suppressor Protein p53

Oral mucositis (OM) is one of the main problems in almost all patients undergoing head and neck radiotherapy (RT). Owning to the antioxidant and anti-inflammatory properties of curcumin, the effect of both oral and topical formulations of curcumin was assessed on radiation-induced OM (ROM) in this study.. The safety and efficacy of curcumin mouthwash 0.1% (w/v) and curcumin-nanocapsule were evaluated in ameliorating severity and pain/burning associated with OM during RT. The current randomized, placebo-controlled trial was conducted on 37 patients with head and neck cancers. Patients with grades 1 to 3 of ROM were randomized to receive one of the three interventions: curcumin mouthwash (0.1% w/v); Sinacurcumin soft gel containing 40 mg curcuminoids as nano-micelles (SinaCurcumin®40); or placebo mouthwash with a similar transparent appearance to curcumin mouthwash for 1 min three times daily during RT. Study evaluations were conducted at baseline and weekly thereafter for up to 3 weeks using the Numeric rating scale (NRS) and world health organization (WHO) scale.. Among the 45 patients randomized, 37 (mean (SD) age of 53.36 (15.99) years; 14 [37.8%] women) completed the treatment according to the protocol. Patients treated with either oral or topical curcumin showed a significantly reduced severity and burning related to OM during the first 3 weeks after administration (P-Value < 0.001) as compared with the placebo. At study termination, more than 33% of subjects utilizing curcumin mouthwash and 15% of patients utilizing curcumin-nanocapsule remained ulcer free while all of the placebo-receiving subjects had OM. The reduction of NRS and WHO scale between curcumin groups was comparable without significant differences.. Both curcumin mouthwash and nanocapsule were effective, safe, and well-tolerated in the treatment of radiation-induced OM. Higher doses of curcumin and larger sample sizes can be used for further investigation in future studies.. https://irct.ir/ IRCT20190810044500N17 (13/08/2021).

Topics: Curcumin; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mouthwashes; Nanocapsules; Stomatitis

To assess the effect of a mucoadhesive herbal medicine containing curcuminoids and a glycerinated extract of Bidens pilosa L. (FITOPROT) in association with photobiomodulation (PBM) therapy and a Preventive Oral Care Program (POCP) compared to PBM and POCP in the treatment of radiotherapy (RT)-induced oral mucositis (ROM) and in the quality of life of these patients.. A double-blind clinical trial was performed with head and neck cancer patients undergoing RT or chemoradiotherapy. Participants were randomized into two groups: Group 1 (n=27): PBM and POCP; and Group 2 (n=25): PBM, POCP and FITOPROT. The PBM protocol was daily irradiation, 660 nm, 25mW, 0.25 J/point from the first until the last day of RT. The FITOPROT was used as mouthwash twice a day. ROM was evaluated based on the scales of the World Health Organization and National Cancer Institute. The quality of life was evaluated using the University of Washington Questionnaire, OHIP-14 and Patient-Reported Oral Mucositis Symptom Scale. The MMAS-8 questionnaire was used to evaluated the adherence to POCP and FITOPROT. Data were collected at baseline, 7. No statistical differences were found between the groups for the ROM evaluation. Both groups experienced worsening of the quality of life during the RT. No statistically significant differences between groups were observed for any of the instruments evaluated.. The results suggest that PBM associated with FITOPROT and POCP control the severity of ROM and stabilize the QoL of patients with head and neck cancer.. Brazilian Registry of Clinical Trials (ReBEC-RBR-9vddmr; UTN code: U1111-1193-2066), registered in August 8th, 2017.

Topics: Bidens; Curcuma; Head and Neck Neoplasms; Humans; Low-Level Light Therapy; Plant Extracts; Quality of Life; Stomatitis

Purpose This study aimed to compare the efficacy of Antimicrobial Photodynamic Therapy (aPDT) with 300 µmol/L of methylene blue and 8 µmol/L of curcumin on oral candidiasis patients with HNSCC undergoing treatment. Methods A two-arm, single-blind clinical trial was performed. Following verification for eligibility (n = 447), 108 patients were included in the study. The study consisted of a group that received aPDT with methylene blue (n = 57) and another that received aPDT with curcumin (n = 51). The patients rinsed their mouths with an aqueous solution of 300 µmol/L of methylene blue and 8 µmol/L of curcumin in four sessions, and then the lesion was scraped for the subsequent RT-qPCR. The primary outcome was that no cure was presented for oral candidiasis after treatment. The secondary result was reducing the number of sites affected by oral candidiasis. Results There was no difference in treatment failure evaluated by the necessity of drug prescription or Candida sp DNA quantification. However, clinically the methylene blue protocol reduced the number of infected anatomical sites compared to the curcumin protocol. Conclusion Methylene blue aPDT reduced the number of infected anatomical sites compared to curcumin.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Candidiasis, Oral; Curcumin; Head and Neck Neoplasms; Humans; Methylene Blue; Photochemotherapy; Photosensitizing Agents; Single-Blind Method

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

One of the most prevalent complications of chemotherapy and radiotherapy is oral mucositis (OM) and manifests as erythema and ulceration. Curcumin is one of the components of turmeric and possesses anti-inflammatory and anti-oxidative features. Some of studies have proved the effectiveness of Curcumin in OM. This study aimed to investigate the effects of nanomicelle Curcumin on OM related chemotherapy and head and neck radiotherapy.. In this clinical trial study, 50 patients underwent chemotherapy with or without head and neck radiotherapy were divided into study and control group. The study group was received Curcumin nanomicelle capsules 80 mg twice a day and the control group took placebo two times a day for 7 weeks and the severity and pain of OM was measured.. Oral mucositis severity in control group in the first (P = 0.010), fourth (P = 0.022) and seventh (P < 0.001) weeks were significantly more than the study group. Pain grade in study group was lower than control group only in the seventh week. (P = 0.001) Additionally, NRS incremental gradient in control group was more than study group. OM severity in patients who underwent only chemotherapy in the control group were significantly more than the study group in all weeks. In patients who were under chemotherapy and head and neck radiotherapy, OM in control group was significantly more intense than the study group only in the fourth and seventh weeks.. Nabomicelle Curcumin capsules is effective on prevention and treatment of head and neck radiotherapy and especially chemotherapy induced OM.. Registered 12 February 2019 at Iranian Registry of Clinical Trials (IRCT). IRCT code: IRCT20100101002950N6 . https://en.irct.ir/trial/36665 . GUMS ethical code: IR.Gums.Rec.1397.296.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antineoplastic Agents; Capsules; Cisplatin; Curcuma; Curcumin; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Iran; Male; Middle Aged; Plant Extracts; Plants, Medicinal; Radiation Injuries; Radiotherapy; Stomatitis

Oral mucositis (OM) is a complication of head and neck cancer (HNC) therapy with negative impact on the quality of life. Although definitive treatment has not yet been established, there is interest towards the use of natural compounds owing to their few side effects. Curcumin has a variety of biological and pharmacological properties including anticancer and anti-inflammatory effects.. The aim of this study is to evaluate the effect of curcumin in the form of nanomicelle on OM in HNC patients receiving radiotherapy.. In this clinical trial, 32 HNC patients were allocated to case and control groups, and respectively received nanocurcumin or placebo during radiotherapy.. We found a statistically significant difference in the severity of mucositis between the 2 groups at all visits. In contrast to the control-group patients, who all developed OM in the 2nd week of radiotherapy, only 32% of the case group developed OM with no obvious oral or systemic side effects.. Our data show that nanomicelle curcumin is an effective agent in the prevention of OM or reducing its severity. Thus, the administration of nanocurcumin can be considered as a reasonable approach to hinder the development of OM in HNC patients requiring radiotherapy.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; Iran; Male; Middle Aged; Stomatitis; Treatment Outcome

Radiation-induced oral mucositis is an acute morbidity seen in patients undergoing treatment for head and neck cancers. In this study, we evaluated the efficacy of turmeric in preventing radiation-induced mucositis.. This was a single-blinded, randomized, controlled clinical trial and was conducted with head and neck cancer patients requiring 70 Gy of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week). Eligible patients (n = 80) were randomly assigned to receive either turmeric gargle (n = 40) or povidone-iodine ([n = 40] active comparator condition) during chemo/radiotherapy during the period of treatment. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7-week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment.. This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points (P< 0.001 toP< 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis (P< 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks (P< 0.01) and reduced change in body weight (P< 0.001).. Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment.

Topics: Adult; Aged; Anti-Infective Agents, Local; Carboplatin; Chemoradiotherapy; Curcuma; Female; Head and Neck Neoplasms; Humans; Incidence; Male; Middle Aged; Mouthwashes; Povidone-Iodine; Radiation Injuries; Single-Blind Method; Stomatitis; Time Factors

The study objective was to assess the effectiveness of a turmeric- and sandal wood oil-containing cream [Vicco(®) turmeric cream (VTC); Vicco Laboratories, Parel, India] on radiodermatitis in patients with head and neck cancer undergoing radiotherapy.. A total of 50 patients with head and neck cancer requiring >60 Gy of curative radiotherapy/chemoradiotherapy were enrolled in the study. The volunteers were randomly divided into two groups of 25 patients. Group 1 was assigned to a topical application of Johnson's(®) baby oil (Johnson & Johnson Ltd, Baddi, India) and Group 2 for VTC. Prophylactic application of the cream was initiated on Day 1 and continued every day until 2 weeks after the end of treatment. Both agents were symmetrically applied within the irradiated field five times a day, and the acute skin reactions were assessed twice weekly in accordance with the Radiation Therapy Oncology Group scores by an investigator who was unaware of the details.. The incidence of radiodermatitis increased with the exposure to radiation and was the highest in both groups at Week 7. However, a significant reduction in grades of dermatitis were seen in cohorts applying VTC at all time points, including 2 weeks post radiotherapy (p < 0.015 to p < 0.001). The occurrence of Grade 3 dermatitis was lower in the cohorts using VTC and was statistically significant (p < 0.01). Additionally, follow-up observations 2 weeks after the completion of radiotherapy also showed a reduced degree of radiodermatitis in cohorts applying VTC, which was significant (p = 0.015).. VTC is shown to be effective in preventing radiodermatitis and needs to be validated in larger double-blind trials.. For the first time, this study shows that the turmeric- and sandal oil-based cream was effective in preventing radiation-induced dermatitis.

Topics: Administration, Topical; Curcuma; Double-Blind Method; Female; Head and Neck Neoplasms; Humans; India; Male; Middle Aged; Ointments; Phytotherapy; Pilot Projects; Plant Oils; Radiodermatitis; Sesquiterpenes; Treatment Outcome

Curcumin has been isolated from the rhizomes of Curcuma longa. Over the years, it has shown outstanding therapeutic potential in various human disorders, including cancers.. The aim is to study curcumin's effects on the apoptosis signaling pathway in the head and neck squamous cell carcinoma (HNSCC) cell line HN5.. The cytotoxicity of curcumin on HN5 cells were assessed. In addition, HN5 cells were also treated with curcumin to evaluate its effect on the caspase-8, -9, Bcl-2, Bax, and Stat3 gene expressions.. The results exhibited that cell viability reduced following curcumin treatment in a concentration- dependent manner. Curcumin treatment caused decreased expression of Bcl2, with simultaneous upregulation of the Bax/Bcl2 ratio. Curcumin increased caspase-9 expression, did not affect caspase-8, and decreased Stat3 expression. The induction of the mitochondria-dependent apoptosis pathway of curcumin happened by modulating the expression of Bcl2 and Bax genes, resulting in the caspase-9 activation. Furthermore, curcumin decreased the expression of the Stat3 in HN-5 cells.. In conclusion, curcumin showed marked anticancer effects in the HN-5 cell line by modulating Stat-3; Bax/Bcl-2 expression in vitro.

Topics: bcl-2-Associated X Protein; Caspase 8; Caspase 9; Cell Line; Curcumin; Head and Neck Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; Squamous Cell Carcinoma of Head and Neck

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

This study evaluated the feasibility of curcumin and docetaxel (DTX) combination therapy for head and neck squamous cell carcinoma (HNSCC). Animal assay demonstrated DTX has certain limitations in improving immunosuppressive microenvironment. Treatment with curcumin overcame this inhibition and reduced tumor progression. Curcumin synergized DTX showed significantly greater reduction in tumor burden than either treatment alone via down-regulation of MDSCs, M2 macrophages and up-regulation of CD8

Topics: Animals; CD8-Positive T-Lymphocytes; Curcumin; Docetaxel; Head and Neck Neoplasms; Humans; Immunity; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

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

Despite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug.. We carried out the western blot and small interfering RNA (siRNA) transfection assay to evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immunofluorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4-nitroquinoline-1-oxide (4-NQO) oral cancer model.. We found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8. These results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.

Topics: Animals; CD8-Positive T-Lymphocytes; Curcumin; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Lymphocytes, Tumor-Infiltrating; Mice; Tumor Microenvironment

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

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

Natural compounds can modulate all three major phases of carcinogenesis. The role of the natural compounds such as resveratrol (RSV) and curcumin (CRM) in modulation of anticancer potential of platinum-based drugs (CisPt) is still a topic of considerable debate. In order to enhance head and neck cancer (HNSCC) cells' sensitivity to the cytotoxic effects of CisPt combined treatments with RSV or CRM were used. The study aim was to evaluate how the RSV or CRM associated to CisPt treatment modulated some cellular processes such as proliferation, P21 gene expression, apoptotic process, and cell cycle development in HNSCC tumor cell line (PE/CA-PJ49) compared to a normal cell line (HUVEC). The results showed that RSV or CRM treatment affected the viability of tumor cells more than normal cells. These natural compounds act against proliferation and sustain the effects of cisplatin by cell cycle arrest, induction of apoptosis and amplification of P21 expression in tumor cells. In conclusion, using RSV or CRM as adjuvants in CisPt therapy might have a beneficial effect by supporting the effects induced by CisPt.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Cell Line, Tumor; Cell Survival; Cisplatin; Curcumin; Head and Neck Neoplasms; Humans; Resveratrol

The deregulated alternative splicing of key glycolytic enzyme, Pyruvate Kinase muscle isoenzyme (PKM) is implicated in metabolic adaptation of cancer cells. The splicing switch from normal PKM1 to cancer-specific PKM2 isoform allows the cancer cells to meet their energy and biosynthetic demands, thereby facilitating the cancer cells growth. We have investigated the largely unexplored epigenetic mechanism of PKM splicing switch in head and neck cancer (HNC) cells. Considering the reversible nature of epigenetic marks, we have also examined the utility of dietary-phytochemical in reverting the splicing switch from PKM2 to PKM1 isoform and thereby inhibition of HNC tumorigenesis.. We present HNC-patients samples, showing the splicing-switch from PKM1-isoform to PKM2-isoform analyzed via immunoblotting and qRT-PCR. We performed methylated-DNA-immunoprecipitation to examine the DNA methylation level and chromatin-immunoprecipitation to assess the BORIS (Brother of Regulator of Imprinted Sites) recruitment and polII enrichment. The effect of dietary-phytochemical on the activity of denovo-DNA-methyltransferase-3b (DNMT3B) was detected by DNA-methyltransferase-activity assay. We also analyzed the Warburg effect and growth inhibition using lactate, glucose uptake assay, invasion assay, cell proliferation, and apoptosis assay. The global change in transcriptome upon dietary-phytochemical treatment was assayed using Human Transcriptome Array 2.0 (HTA2.0).. Here, we report the role of DNA-methylation mediated recruitment of the BORIS at exon-10 of PKM-gene regulating the alternative-splicing to generate the PKM2-splice-isoform in HNC. Notably, the reversal of Warburg effect was achieved by employing a dietary-phytochemical, which inhibits the DNMT3B, resulting in the reduced DNA-methylation at exon-10 and hence, PKM-splicing switch from cancer-specific PKM2 to normal PKM1. Global-transcriptome-analysis of dietary-phytochemical-treated cells revealed its effect on alternative splicing of various genes involved in HNC.. This study identifies the epigenetic mechanism of PKM-splicing switch in HNC and reports the role of dietary-phytochemical in reverting the splicing switch from cancer-specific PKM2 to normal PKM1-isoform and hence the reduced Warburg effect and growth inhibition of HNC. We envisage that this approach can provide an effective way to modulate cancer-specific-splicing and thereby aid in the treatment of HNC.

Topics: Aged, 80 and over; Alternative Splicing; Antineoplastic Agents; Carcinoma, Squamous Cell; Carrier Proteins; Cell Line, Tumor; Curcumin; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3B; DNA-Binding Proteins; Epigenesis, Genetic; Female; Glycolysis; Head and Neck Neoplasms; Humans; Male; Membrane Proteins; Middle Aged; Phytochemicals; Protein Isoforms; Pyruvate Kinase; Thyroid Hormone-Binding Proteins; Thyroid Hormones

Combination therapy has been conferred with manifold assets leveraging the synergy of different agents to achieve a sufficient therapeutic outcome with lower administered drug doses and reduced side effects. The therapeutic potency of a self-assembling peptide hydrogel for the co-delivery of doxorubicin and curcumin was assessed against head and neck cancer cells. The dual loaded peptide hydrogel enabled control over the rate of drug release based on drug's aqueous solubility. A significantly enhanced cell growth inhibitory effect was observed after treatment with the combination drug-loaded hydrogel formulations compared to the respective combination drug solution. The synergistic pharmacological effect of selected hydrogel formulations was further confirmed with enhanced apoptotic cell response, interference in cell cycle progression, and significantly altered apoptotic/anti-apoptotic gene expression profiles obtained in dose levels well below the half-maximal inhibitory concentrations of both drugs. The in vivo antitumor efficacy of the drug-loaded peptide hydrogel formulation was confirmed in HSC-3 cell-xenografted severe combined immunodeficient mice and visualized with μCT imaging. Histological and terminal deoxynucleotidyl transferase dUTP nick end labeling assay analyses of major organs were implemented to assess the safety of the topically administered hydrogel formulation. Overall, results demonstrated the therapeutic utility of the dual drug-loaded peptide hydrogel as a pertinent approach for the local treatment of head and neck cancer.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Doxorubicin; Drug Delivery Systems; Female; Flow Cytometry; Head and Neck Neoplasms; Humans; Hydrogels; Mice; Mice, SCID; Microscopy, Atomic Force; Peptides; Rheology; Xenograft Model Antitumor Assays

Retinoid X receptor-α (RXRα) is a kind of nuclear receptor and is a target of cancer prevention and treatment in various types of cancers. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis, tumor recurrence and chemotherapy resistance. So far, the mechanism how RXRα regulates CSCs remains unknown. In the present study, we found that RXRα was upregulated in head and neck squamous cell carcinoma (HNSCC) tissues and the enriched HNSCC CSCs. Overexpression of RXRα was able to expand the CSC-like properties in HNSCC cells, whereas knockdown of RXRα could repress the stemness respectively. Meanwhile, low doses of cisplatin (CDDP) increased the CSC-like properties and RXRα expression in HNSCC cells. Also, Wnt signaling pathway played a significant role in CDDP-induced CSCs. Simultaneously, curcumin, a plant polyphenol, which is an effective anticancer compound, exhibited an inhibitory effect in the HNSCC CSCs induced by CDDP in vitro and in vivo. Via inhibition of RXRα, curcumin suppressed CSC-like phenotypes induced by CDDP. These findings may suggest a novel mechanism for HNSCC treatment.

Topics: Adult; Aged; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Female; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplastic Stem Cells; Retinoid X Receptor alpha; Squamous Cell Carcinoma of Head and Neck

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Catechin; Curcumin; Female; Head and Neck Neoplasms; Humans; Killer Cells, Natural; Lung Neoplasms; Macrophages; Mice; Mice, Inbred C57BL; Mice, Nude; Papillomaviridae; Papillomavirus Infections; Resveratrol; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Head and neck squamous cell carcinoma (HNSCC) is associated with low survival, and the current aggressive therapies result in high morbidity. Nutraceuticals are dietary compounds with few side effects. However, limited antitumor efficacy has restricted their application for cancer therapy. Here, we examine combining nutraceuticals, establishing a combination therapy that is more potent than any singular component, and delineate the mechanism of action. Three formulations were tested: GZ17-S (combined plant extracts from Arum palaestinum, Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-6.02 (3 synthetic components of GZ17S; curcumin, harmine and isovanillin). We tested the formulations on HNSCC proliferation, migration, invasion, angiogenesis, macrophage viability and infiltration into the tumor and tumor apoptosis. GZ17-6.02, the most effective formulation, significantly reduced in vitro assessments of HNSCC progression. When combined with cisplatin, GZ17-6.02 enhanced anti-proliferative effects. Molecular signaling cascades inhibited by GZ17-6.02 include EGFR, ERK1/2, and AKT, and molecular docking analyses demonstrate GZ17-6.02 components bind at distinct binding sites. GZ17-6.02 significantly inhibited growth of HNSCC cell line, patient-derived xenografts, and murine syngeneic tumors in vivo (P < 0.001). We demonstrate GZ17-6.02 as a highly effective plant extract combination and pave the way for future clinical application in HNSCC.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arum; Benzaldehydes; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Combined Modality Therapy; Curcuma; Curcumin; Dietary Supplements; ErbB Receptors; Harmine; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Peganum; Plant Extracts; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Globally, head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and represents approximately 6% of all diagnosed cancers. The use of anti-cancer drugs, such as docetaxel, doxorubicin (DOX), 5-fluorouracil (5-FU), and cisplatin (diammine dichloroplatinum(II), CDDP), is limited due to their non-specificity, drug resistance, and toxicity. A combinatorial approach may improve the efficacy of these chemotherapeutic drugs and reduce their non-specific toxicities. In the present study, curcumin, an anti-cancer phytochemical, was used in combination with 5-FU, doxorubicin, and cisplatin and their combinatorial effect on the HNSCC cell line NT8e was investigated. Our results showed that the combination of 5-FU or DOX with curcumin exhibited significant growth inhibition and enhanced apoptosis in NT8e cancer cells. Treatment with 5-FU or DOX in combination with curcumin induced apoptosis by inhibiting Bcl-2 and increasing Bax, caspase-3, and poly-ADP ribose polymerase (PARP) in NT8e cells. This was further confirmed through apoptotic characteristic features in cells, such as membrane blebbing, nuclear condensation, and cell shrinkage, as observed by DAPI staining and through decreased red/green fluorescence by JC-1. These two combinations also exhibited cell cycle growth arrest at the G1/S phase, which was confirmed by downregulation of cyclins (D1, E2, B1, and A2), CDK2, and increased p21 levels. In addition, curcumin exposure along with 5-FU or DOX inhibited cell proliferation through the downregulation of EGFR-ERK1/2 signaling molecules. Overall, our data demonstrates the promising therapeutic potential and underlying mechanisms of curcumin with 5-FU/DOX combinations as a new treatment modality for head and neck cancer management.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cisplatin; Curcumin; Doxorubicin; ErbB Receptors; Fluorouracil; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Signal Transduction; Squamous Cell Carcinoma of Head and Neck

Despite its high promise for cancer prevention and therapy, the potential utility of curcumin in cancer is compromised by its low bioavailability and weak potency. The purpose of the current study was to assess the in vitro and in vivo efficacy and pharmacokinetic parameters of the potent curcumin analogue FLLL12 in SCCHN and identify the mechanisms of its antitumor effect. IC50 values against a panel of one premalignant and eight malignant head and neck cancer cell lines as well as apoptosis assay results suggested that FLLL12 is 10- to 24-fold more potent than natural curcumin depending on the cell line and induces mitochondria-mediated apoptosis. In vivo efficacy (xenograft) and pharmacokinetic studies also suggested that FLLL12 is significantly more potent and has more favorable pharmacokinetic properties than curcumin. FLLL12 strongly inhibited the expression of p-EGFR, EGFR, p-AKT, AKT, Bcl-2, and Bid and increased the expression of Bim. Overexpression of constitutively active AKT or Bcl-2 or ablation of Bim or Bid significantly inhibited FLLL12-induced apoptosis. Further mechanistic studies revealed that FLLL12 regulated EGFR and AKT at transcriptional levels, whereas Bcl-2 was regulated at the translational level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is a potent curcumin analogue with more favorable pharmacokinetic properties that induces apoptosis of head and neck cancer cell lines by inhibition of survival proteins including EGFR, AKT, and Bcl-2 and increasing of the proapoptotic protein Bim.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Availability; Cell Line, Tumor; Curcumin; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Mitochondria; Neoplasm Transplantation; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-2; Reproducibility of Results; RNA, Small Interfering

The purpose of this study is to assess the effect of 5-fluorouracil nanoparticles and curcumin naoparticles on cell proliferation and the expression of the apoptotic marker (caspase 3) in squamous cell carcinoma cell line.. PLGA 5-fluorouracil nanopartciles and PLGA curcumin nanoparticles were prepared and applied for 24 and 48h on human laryngeal squamous carcinoma cell line (Hep-2) as regard IC 50 concentration. MTT assay was used for evaluation of cytotoxicity of prepared nanoparticles. Quantitaive reverse transcriptase polymerase chain reaction (QRT-PCR) was used for the assessment of caspase-3 expression in the treated cell line.. The drug release rate profiles was dependent upon polymer to drug ratio, noting that the higher PLGA polymer ratio to 5-fluprouracil or curcumin drug showed faster release rates. On the other hand, the least PLGA polymer ratio to 5-fluprouracil or curcumin drug showed the slowest release rates. MTT assay revelaed that 5-fluorouracil nanoparticels or curcumin nanoparticels showed a clear cytotoxic effect on Hep-2 cell line compared to non treated cancer cells. The RT-PCR assessment of caspase-3 expression revealed that there was a significant increase in caspase-3 expression in Hep-2 cell line treated with 5-fluorouracil nanoparticles or curcumin compared to non treated cancer cells.. Curcumin nanoparticles could be more active in inducing apoptosis in short term assays (24h) than long term assays (48h) due to differential cellular uptake. While 5-fluorouracil nanoparticles induced higher significant apoptosis in long term (48h) compared to curcumin group.

Topics: Apoptosis; Carcinoma, Squamous Cell; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Fluorouracil; Head and Neck Neoplasms; Humans; Lactic Acid; Laryngeal Neoplasms; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Squamous Cell Carcinoma of Head and Neck

Head and neck squamous cell carcinoma (HNSCC) represents the most frequent malignancy in the head and neck region, and the survival rate has not been improved significantly over the past three decades. It has been reported the infiltrated macrophages contribute to the malignant progression of HNSCC. However, the crosstalk between macrophages and cancer cells remains poorly understood. In the present study, we explored interactions between monocytes/macrophages and HNSCC cells by establishing the direct co-culture system, and found that the crosstalk promoted the migration and invasion of cancer cells by enhancing the invadopodia formation through a CCL2/EGF positive feedback loop. Our results demonstrated HNSCC cells educated monocytes into M2-like macrophages by releasing C-C motif chemokine ligand 2 (CCL2, or MCP-1). And the M2-like macrophages secreted epithelial growth factor (EGF), which increased the motility of HNSCC cells by enhancing the invadopodia formation. These subcellular pseudopodia degraded extracellular matrix (ECM), facilitating tumor local invasion and distant metastasis. Moreover, EGF up-regulated CCL2 expression in HNSCC cells, which recruited monocytes and turned them into M2-like macrophages, thus forming a positive feedback paracrine loop. Finally, we reported that curcumin, a powerful natural drug, suppressed the production of EGF and CCL2 in macrophages and cancer cells, respectively, blocking the feedback loop and suppressing the migration and invasion of HNSCC cells. These results shed light on the possibilities and approaches based on targeting the crosstalk between cancer cells and monocytes/macrophages in HNSCC for potential cancer therapy.

Topics: Carcinoma, Squamous Cell; Cell Communication; Cell Differentiation; Cell Movement; Cell Polarity; Chemokine CCL2; Curcumin; Epidermal Growth Factor; Feedback, Physiological; Head and Neck Neoplasms; Humans; Macrophages; Monocytes; Neoplasm Invasiveness; Squamous Cell Carcinoma of Head and Neck

Head and neck squamous cell carcinoma (HNSCC) and acute myeloid leukemia are the major causes of mortality and morbidity in Fanconi anemia (FA) patients. The objective of this study was to investigate the antineoplastic activity of PB, an antineoplastic nutrient mixture (containing quercetin, curcumin, green tea, cruciferex and resveratrol) on human FA HNSCC in vitro and in vivo. Human FA HNSCC cell line OHSU-974 (Fanconi Anemia Research Fund) was cultured in RPMI medium supplemented with 20% FBS and anti-biotics. At near confluence, cells were treated in triplicate with different concentrations of PB: 0, 10, 25, 50, 75 and 100 µg/ml. Cells were also treated with PMA to induce MMP-9 activity. Cell proliferation was detected by MTT assay, secretion of MMPs by gelatinase zymography, invasion through Matrigel, migration by scratch test and morphology by hematoxylin and eosin (H&E) staining. In vivo, athymic male nude mice (n=12) were inoculated with 3x106 OHSU-974 cells subcutaneously and randomly divided into two groups: group A was fed a regular diet and group B a regular diet supplemented with 1% PB. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. NM inhibited the growth of OHSU-974 tumor by 67.6% (p<0.0001) and tumor burden by 63.6% (p<0.0001). PB demonstrated dose-dependent inhibition of cell proliferation, with 27% (p=0.0003) and 48% (p=0.0004) toxicity at 75 and 100 µg/ml, respectively. Zymography revealed MMP-2 and PMA-induced MMP-9 secretion. PB suppressed secretion of both MMPs in a dose-dependent manner, with total block of both at 50 µg/ml. PB inhibited cell migration (by scratch test) and OHSU-974 invasion through Matrigel in a dose-dependent fashion with total block at 50 µg/ml. H&E staining showed no morphological changes below 50 µg/ml. The results suggest that PB has potential therapeutic use in the treatment of human FA HNSCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dietary Supplements; Disease Models, Animal; Fanconi Anemia; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Nude; Phytochemicals; Phytotherapy; Quercetin; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes; Tea; Xenograft Model Antitumor Assays

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with 600,000 new cases every year worldwide. Although chemotherapeutics exist, five-year survival is only 50%. New strategies to overcome drug resistance are required to improve HNSCC treatment. Curcumin-difluorinated (CDF), a synthetic analog of curcumin, was packaged in liposomes and used to evaluate growth inhibition of cisplatin resistant HNSCC cell lines CCL-23R and UM-SCC-1R generated from the parental cell lines CCL-23 and UM-SCC-1 respectively. Growth inhibition in vitro and expression levels of the CD44 (cancer stem cell marker), cytokines, and growth factors were investigated after liposomal CDF treatment. The in vivo growth inhibitory effect of liposomal CDF was evaluated in the nude mice xenograft tumor model of UM-SCC-1R and the inhibition of CD44 was measured. Treatment of the resistant cell lines in vitro with liposomal CDF resulted in a statistically significant growth inhibition (p < 0.05). The nude mice xenograft study showed a statistically significant tumor growth inhibition of UM-SCC-1R cells and a reduction in the expression of CD44 (p < 0.05), indicating an inhibitory effect of liposomal CDF on CSCs. Our results demonstrate that delivery of CDF through liposomes may be an effective method for the treatment of cisplatin resistant HNSCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Cytokines; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Hydrocarbons, Fluorinated; Liposomes; Mice, Nude; Neoplastic Stem Cells; Reverse Transcriptase Polymerase Chain Reaction; Tumor Burden; Xenograft Model Antitumor Assays

SIRT1 is one of seven mammalian homologs of Sir2 that catalyzes NAD(+)-dependent protein deacetylation. The aim of the present study is to explore the effect of SIRT1 small molecule activator on the anticancer activity and the underlying mechanism. We examined the anticancer activity of a novel oral agent, curcumin, which is the principal active ingredient of the traditional Chinese herb Curcuma Longa. Treatment of FaDu and Cal27 cells with curcumin inhibited growth and induced apoptosis. Mechanistic studies showed that anticancer activity of curcumin is associated with decrease in migration of HNSCC and associated angiogenesis through activating of intrinsic apoptotic pathway (caspase-9) and extrinsic apoptotic pathway (caspase-8). Our data demonstrating that anticancer activity of curcumin is linked to the activation of the ATM/CHK2 pathway and the inhibition of nuclear factor-κB. Finally, increasing SIRT1 through small molecule activator curcumin has shown beneficial effects in xenograft mouse model, indicating that SIRT1 may represent an attractive therapeutic target. Our studies provide the preclinical rationale for novel therapeutics targeting SIRT1 in HNSCC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Enzyme Activation; Head and Neck Neoplasms; Humans; Mice, Nude; Mitochondria; Signal Transduction; Sirtuin 1; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

In oncology, an emerging paradigm emphasises molecularly targeted approaches for cancer prevention and therapy and the use of adjuvant chemotherapeutics to overcome cisplatin limitations. Owing to their safe use, some polyphenols, such as curcumin, modulate important pathways or molecular targets in cancers. This paper focuses on curcumin as an adjuvant molecule to cisplatin by analysing its potential implications on the molecular targets, signal transducer and activator of transcription 3 (STAT3) and NF-E2 p45-related factor 2 (Nrf-2), in tumour progression and cisplatin resistance in vitro and the adverse effect ototoxicity in vivo.. The effects of curcumin and/or cisplatin treatment have been evaluated in head and neck squamous cell carcinoma as well as in a rat model of cisplatin-induced ototoxicity by using immunofluorescence, western blot, and functional and morphological analysis.. This study demonstrates that curcumin attenuates all stages of tumour progression (survival, proliferation) and, by targeting pSTAT3 and Nrf-2 signalling pathways, provides chemosensitisation to cisplatin in vitro and protection from its ototoxic adverse effects in vivo.. These results indicate that curcumin can be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (STAT3 and Nrf2) and, at the same time, reduce cisplatin-related ototoxic adverse effects.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Curcumin; Drug Resistance, Neoplasm; Evoked Potentials, Auditory, Brain Stem; Head and Neck Neoplasms; Hearing Loss; Humans; Male; NF-E2-Related Factor 2; Phosphorylation; Rats; Rats, Wistar; Signal Transduction; STAT3 Transcription Factor

The natural compound curcumin has been investigated as an anticancer agent in many cellular systems, in animal models and in the clinic. The overriding negative characteristics of curcumin are its low solubility, weak potency and poor bioavailability. We have examined the efficacy and mechanism of action of a synthetic curcumin analog, UBS109, in head and neck squamous cell carcinoma. By nephelometry, this analog exhibits considerably greater solubility than curcumin. Pharmacokinetic studies of a single oral dose of UBS109 in mice revealed that peak plasma concentrations were reached at 0.5 hours post-dose (Tmax) with average plasma concentrations (Cmax) of 131 and 248 ng/mL for oral doses of 50 and 150 mg/kg, respectively. The terminal elimination half-lives (T½) for these doses averaged 3.7 and 4.5 hours, respectively. In both in vitro and in vivo studies, we found that UBS109 decreased the levels of phosphorylated IKKβ and phosphorylated p65 and, unexpectedly, increased the levels of phosphorylated IκBα by Western blot analysis. These observations may suggest that UBS109 suppresses tumor growth through, in part, inhibition of NF-κB p65 phosphorylation by PKAc and not through IκBα. Finally, we demonstrate that UBS109 is efficacious in retarding the growth of Tu212 (head and neck) squamous cell carcinoma (SCC) xenograft tumors in mice and may be useful for treating head and neck SCC tumors.

Topics: Animals; Antineoplastic Agents; Biological Availability; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Curcumin; Female; Half-Life; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Mice, Inbred ICR; Mice, Nude; Neoplasm Proteins; Phosphorylation; Piperidones; Protein Processing, Post-Translational; Pyridines; Random Allocation; Specific Pathogen-Free Organisms; Squamous Cell Carcinoma of Head and Neck; Transcription Factor RelA; Tumor Burden; Xenograft Model Antitumor Assays

Chemotherapy constitutes the standard modality of treatment for localized head and neck squamous cell carcinomas (HNSCC). However, many patients fail to respond and relapse after this treatments due to the acquisition of chemo-resistance. Therefore, there is an urgent need to develop novel drugs that could reverse the resistant phenotype. Curcumin, the constituent of the spice turmeric has been shown to have anti-inflammatory, anti-oxidant and anti-proliferative properties in several tumor types. However, use of curcumin has been limited due to its poor bio-absorption. Recently, a novel class of curcumin analogs, based on diarylidenylpiperidones (DAP), has been developed by incorporating a piperidone link to the beta-diketone structure and fluoro substitutions on the phenyl groups. In this study, we evaluated the effectiveness of H-4073, a parafluorinated variant of DAP, using both in vitro and in vivo head and neck cancer models. Our results demonstrate that H-4073 is a potent anti-tumor agent and it significantly inhibited cell proliferation in all the HNSCC cell lines tested in a dose-dependent manner. In addition, pretreatment of cisplatin-resistant HNSCC cell lines with H-4073 significantly reversed the chemo-resistance as observed by cell viability assay (MTT), apoptosis assay (Annexin V binding) and cleaved caspase-3 (Western blot). H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis. In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity. Interestingly, H-4073 inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell function. Taken together, our results suggest that H-4073 is a potent anti-tumor agent and it can be used to overcome chemotherapy resistance in HNSCC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cisplatin; Curcumin; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Synergism; Head and Neck Neoplasms; Humans; Mice; Neovascularization, Pathologic; Phosphorylation; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

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

Topics: Antineoplastic Agents; Chewing Gum; Curcumin; Head and Neck Neoplasms; Humans

The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-κB accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Proliferation; Curcumin; Drug Synergism; Fluorescent Antibody Technique; Head and Neck Neoplasms; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Phosphorylation; Reactive Oxygen Species; Resveratrol; Salivary Gland Neoplasms; Signal Transduction; Stilbenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

ALDH1(+)CD44(+) cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1(+)CD44(+)-HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1(-)CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1(-)CD44(-)-HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from Spg-miR145-transfected non-TICs/ALDH1(-)CD44(-)-HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1(-)CD44(-)-HNC and this effect could be abrogated by an IL-6-neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145(low)/SOX9(high)/ADAM17(high) phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC.

Topics: 3' Untranslated Regions; ADAM Proteins; ADAM17 Protein; Animals; Base Sequence; Carcinoma, Squamous Cell; Cell Growth Processes; Cell Line, Tumor; Curcumin; Epithelial-Mesenchymal Transition; Head and Neck Neoplasms; Heterografts; Humans; Interleukin-6; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplastic Stem Cells; Promoter Regions, Genetic; Receptors, Interleukin-6; Signal Transduction; SOX9 Transcription Factor; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Head and neck cancer is one of the most morbid human malignancies with an overall poor prognosis and severely compromised quality of life. As a result, there is significant interest in developing adjuvant therapies to augment currently available treatment protocols. Curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways. In this study, we showed that curcumin inhibits head and neck cancer cell growth through reduction of PGE2 receptor EP4 gene expression. Blockade of AMP-dependent kinase (AMPK), and p38 MAPK by either chemical inhibitors or siRNAs antagonized the inhibitory effect of curcumin on EP4 expression, which was reversed by metformin, an activator of AMPK. Curcumin induced PGC-1α protein that was blocked by compound C and SB239063. Silencing of PGC-1α reversed the effect of curcumin on EP4 protein. Overexpression of EP4 overcame the effect of curcumin on head and neck cancer cell growth. In addition, curcumin reduced Sp1 protein. Overexpression of Sp1 resisted the inhibitory effect of curcumin on EP4 promoter activity and protein expression. Interestingly, overexpression of PGC-1α further enhanced the inhibitory effect of curcumin on Sp1 protein expression that was blocked by SB239063. In conclusion, this study shows that curcumin inhibits EP4 gene expression dependent of AMPKα and p38 MAPK activation, this leads to reduction of Sp1 protein and binding to specific area in the EP4 gene promoter. The cross talks of AMPKα and p38 MAPK signaling, the kinase-mediated PGC-1α expression and reciprocity of PGC-1α and Sp1 enhance this process. This ultimately results in inhibition of head and neck cancer cell proliferation.

Topics: Adenylate Kinase; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Curcumin; Down-Regulation; Enzyme Activation; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Metformin; Molecular Targeted Therapy; p38 Mitogen-Activated Protein Kinases; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Prostaglandin E, EP4 Subtype; RNA Interference; Signal Transduction; Transcription Factors

Laryngopharyngeal reflux (LPR) is associated with inflammatory and neoplastic airway diseases. Gastric pepsin internalized by airway epithelial cells during reflux contributes to oxidative stress, inflammation, and carcinogenesis. Several plant extracts and compounds inhibit digestive enzymes and inflammatory or neoplastic changes to the esophagus in models of gastroesophageal reflux. This study examined the potential of chemoprotective phytochemicals to inhibit peptic activity and mitigate pepsin-mediated damage of airway epithelial cells.. Cultured human laryngeal and hypopharyngeal epithelial cells were pretreated with curcumin (10 micromol/L), ecabet sodium (125 microg/mL), and anthocyanin-enriched black-raspberry extract (100 microg/mL) 30 minutes before treatment with pepsin (0.1 mg/mL; 1 hour; pH 7). Controls were treated with media pH 7 or pepsin pH 7 without phytochemicals. Cell damage and proliferative changes were assessed by electron microscopy, cell count, thymidine analog incorporation, and real-time polymerase chain reaction array. Pepsin inhibition was determined by in vitro kinetic assay.. Micromolar concentrations of curcumin, ecabet sodium, and black-raspberry extract inhibited peptic activity and pepsin-induced mitochondrial damage and hyperproliferation. Curcumin abrogated pepsin-mediated depression of tumor suppressor gene expression and altered the subcellular localization of pepsin following endocytosis.. Several phytochemicals inhibit the pepsin-mediated cell damage underlying inflammatory or neoplastic manifestations of LPR. Dietary supplementation or adjunctive therapy with phytochemicals may represent novel preventive or therapeutic strategies for LPR-attributed disease.

Topics: Anthocyanins; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Curcumin; DNA Damage; Drug Therapy, Combination; Epithelial Cells; Gene Expression Regulation; Genes, Tumor Suppressor; Head and Neck Neoplasms; Humans; Immunohistochemistry; Laryngopharyngeal Reflux; Microscopy, Electron, Transmission; Mitochondria; Pepsin A; Phytochemicals

Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV (-) cell lines was significantly higher than the HPV (+) cell lines used in our study. Notably, all of the HPV (-) cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV (-) cell lines it had no effect on the HPV (+) cells. Based on these findings we employed an orthotopic, HPV (-) HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV (-) HNSCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Chemoprevention; Curcumin; Disease Models, Animal; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Papillomaviridae; Radiation Tolerance; Radiation-Sensitizing Agents; Thioredoxin Reductase 1

Objectives are to examine the efficacy, pharmacokinetics, and toxicology of a synthetic curcumin analog EF31 in head and neck squamous cell carcinoma. The synthesis of EF31 was described for the first time. Solubility of EF24 and EF31 was compared using nephelometric analysis. Human head and neck squamous cell carcinoma Tu212 xenograft tumors were established in athymic nude mice and treated with EF31 i.p. once daily five days a week for about 5-6 weeks. The long term effect of EF31 on the NF-κB signaling system in the tumors was examined by Western blot analysis. EF31 at 25 mg kg(-1), i.p. inhibited tumor growth almost completely. Solubilities of EF24 and EF31 are <10 and 13 μg mL(-1) or <32 and 47 μM, respectively. The serum chemistry profiles of treated mice were within the limits of normal, they revealed a linear increase of C(max). EF31 decreased the level of phosphorylation of NF-κB p65. In conclusion, the novel synthetic curcumin analog EF31 is efficacious in inhibiting the growth of Tu212 xenograft tumors and may be useful for treating head and neck squamous cell carcinoma. The long term EF31 treatment inhibited NF-κB p65 phosphorylation in xenografts, implicating downregulation of cancer promoting transcription factors such as angiogenesis and metastasis.

Topics: Animals; Blotting, Western; Carcinoma, Squamous Cell; Cell Survival; Curcumin; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Phosphorylation; Piperidones; Random Allocation; Signal Transduction; Solubility; Specific Pathogen-Free Organisms; Transcription Factor RelA; Xenograft Model Antitumor Assays

Despite clear results of observational studies linking a diet rich in fruits and vegetables to a decreased cancer risk, large interventional trials evaluating the impact of dietary micronutrient supplementation, mostly vitamins, could not show any beneficial effects. Today it has become clear that a single micronutrient, given in supernutritional doses, cannot match cancer preventive effects of whole fruits and vegetables. In this regard polyphenols came into focus, not only because of their antioxidant potential but also because of their ability to interact with molecular targets within the cells. Because polyphenols occur in many foods and beverages in high concentration and evidence for their anticancer activity is best for tissues they can come into direct contact with, field cancerization predestines upper aerodigestive tract epithelium for cancer chemoprevention by polyphenols. In this paper, we summarize cancer chemopreventive attempts with emphasis on head and neck carcinogenesis and discuss some methodological issues. We present data regarding antimutagenic effects of curcumin and epigallocatechin-3-gallate in human oropharyngeal mucosa cultures exposed to cigarette smoke condensate.

Topics: Antimutagenic Agents; Catechin; Cell Survival; Cells, Cultured; Curcumin; DNA Damage; Head and Neck Neoplasms; Humans; Nicotiana; Polyphenols

To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin.. Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC(50)) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined.. The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin.. FLLL32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Curcumin; Down-Regulation; Head and Neck Neoplasms; Humans; Microbial Sensitivity Tests; Signal Transduction; STAT3 Transcription Factor

To determine whether curcumin would inhibit IκB kinase β (IKKβ) kinase activity and suppress expression of proinflammatory cytokines in head and neck squamous cell carcinoma cancer (HNSCC) patients.. Saliva was collected before and after subjects chewed curcumin tablets. Protein was extracted and IKKβ kinase activity measured. Interleukin (IL)-6 and IL-8 levels in the salivary supernatants were measured by ELISA. IL-6, IL-8, and other interleukin were also measured independently with ELISA to confirm the inhibitory effect of curcumin on expression and secretion of salivary cytokines.. Curcumin treatment led to a reduction in IKKβ kinase activity in the salivary cells of HNSCC patients (P < 0.05). Treatment of UM-SCC1 cells with curcumin as well as with post-curcumin salivary supernatant showed a reduction of IKKβ kinase activity. Significant reduction of IL-8 levels (P < 0.05) was seen in post-curcumin samples from patients with dental caries. Although there was reduced IL-8 expression in 8 of 21 post-curcumin samples of HNSCC patients, the data did not reach statistical significance. Saliva samples from HNSCC patients were also analyzed in a blinded fashion for expression of cytokines. IL-10, IFN-γ, IL-12p70, and IL-2 clustered together, and granulocyte macrophage colony stimulating factor and TNF-α clustered together. Log₁₀ ratio analysis showed decrease in expression of all nine cytokines in both the salivary supernatant and salivary cells of curcumin-treated samples.. Curcumin inhibited IKKβ kinase activity in the saliva of HNSCC patients, and this inhibition correlated with reduced expression of a number of cytokines. IKKβ kinase could be a useful biomarker for detecting the effect of curcumin in head and neck cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; Cytokines; Enzyme Activation; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Male; Middle Aged; Pilot Projects; Protein Kinase Inhibitors; Saliva; Salivary Glands; Squamous Cell Carcinoma of Head and Neck

Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 ± 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line; Cell Movement; Cell Proliferation; Curcumin; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Keratinocytes; Mice; NF-kappa B; Nicotine; Phosphatidylinositol 3-Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Previous experiments have shown that curcumin or cisplatin treatment suppresses growth of head and neck squamous cell carcinoma (HNSCC). To study the potential cooperative effect of both agents, two HNSCC cell lines were treated with curcumin or cisplatin alone or in combination. In vivo studies consisted of intravenous tail vein injection of liposomal curcumin, with intraperitoneal cisplatin, into nude mice growing xenograft HNSCC tumors. Introduction of curcumin and suboptimal concentrations of cisplatin showed a significant suppressive effect compared with treatment with either agent alone. Reduced expression of cyclin D1, IκBα, phospho-IκBα, and IKKβ occurred in cisplatin- and curcumin-treated cell lines. Confocal microscopy showed expression of IKKβ in the nucleus of the cell lines. Chromatin immunoprecipitation assay on DNA isolated from IKKβ immunoprecipitated samples showed PCR amplification of interleukin-8 promoter sequences, a binding site of NFκB, indicating an interaction between IKKβ and NFκB. Curcumin inhibited IKKβ in the cytoplasm and nucleus, leading to reduced NFκB activity, with no effect on phospho-AKT. In vivo studies showed significant growth inhibition of xenograft tumors treated with a combination of liposomal curcumin and cisplatin. The suppressive effect of curcumin was mediated through inhibition of cytoplasmic and nuclear IKKβ, resulting in inhibition of NFκB activity. Cisplatin treatment led to cellular senescence, indicating an effect mediated by p53 activation. The mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of subtherapeutic doses of cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects of cisplatin.

Topics: Animals; Antineoplastic Agents; Base Sequence; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Chromatin Immunoprecipitation; Cisplatin; Curcumin; DNA Primers; Female; Fluorescent Antibody Technique; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Mice; Mice, Nude; NF-kappa B; Polymerase Chain Reaction; Transplantation, Heterologous

To evaluate the effect of curcumin on production of interleukin 6 (IL-6) and 8 (IL-8) in head and neck squamous cell carcinoma (HNSCC) cell lines and to determine the mechanism by which these effects are modulated. Curcumin suppression of HNSCC is believed to be partly due to inhibition of the transcription factor nuclear factor-kappa beta (NF-kappa beta). Interleukin 6 and IL-8 are cytokines induced by NF-kappa beta activation with elevated levels in the serum of patients with HNSCC.. We treated HNSCC cell lines CCL23, CAL27, UM-SCC1, and UM-SCC14A with increasing doses of curcumin and measured IL-6 and IL-8 levels using an enzyme-linked immunosorbent assay.. Levels of NF-kappa beta, Ikappa beta kinase (IKK), and phosphorylated Ikappa beta were analyzed by means of Western blot. The IKK activity was measured in UM-SCC14A cells using an IKK-specific Ikappa beta alpha substrate after treatment with curcumin.. Reverse transcription-polymerase chain reaction was performed to determine the effect of curcumin on the expression of IL-6 and IL-8.. Curcumin treatment resulted in dose-dependent inhibition of IL-6 and IL-8 in all cell lines. All cell lines had similar NF-kappa beta levels; however, UM-SCC1 and UM-SCC14A had significantly higher Ikappa beta kinase levels and required considerably higher doses of curcumin before inhibition of IL-6 and IL-8 occurred. Curcumin treatment resulted in inhibition of IKK activity and inhibition of IL-6 and IL-8 expression.. Curcumin significantly reduces IL-6 and IL-8 levels in HNSCC cell lines. This mechanism appears to be mediated via inhibition of Ikappa beta-kinase activity in the NF-kappa beta pathway. Interleukins 6 and 8 have potential use as biomarkers to measure the efficacy of treatment with curcumin.

Topics: Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Curcumin; Enzyme-Linked Immunosorbent Assay; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Interleukin-6; Interleukin-8; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

To investigate whether curcumin enhances the cytotoxic effect of radiotherapy in head and neck squamous cell carcinoma (HNSCC).. HNSCC cell lines SCC-1, SCC-9, KB, as well as A431 cell line were treated with curcumin, irradiation, or their combination. Cell viability was evaluated by XTT assay. Cyclooxygenase-2 (COX-2), epithelial growth factor receptor (EGFR), and p-Erk1/2 were measured by Western blot analysis. CD-1 athymic nude mice with orthotopic implanted SCC-1 cells, were treated with control diet, curcumin containing diet, local single-dose radiation, or combination.. Curcumin (IC50 range, 15-22 microM) and radiation inhibited cell viability in all cell lines were tested. The combination of curcumin and radiation resulted in additive effect. Curcumin decreased COX-2 expression and inhibited phosphorylation of EGFR in SCC-1 cells. In tumor-bearing mice the combination regimen showed a decrease in both tumor weight (25%, P = .09) and tumor size (15%, P = .23) compared to the nontreated mice.. : Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. A possible mechanism is inhibition of COX-2 expression and EGFR phosphorylation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Curcumin; Cyclooxygenase 2; Dose-Response Relationship, Drug; ErbB Receptors; Flow Cytometry; Head and Neck Neoplasms; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation

The purpose of this study was to determine whether a liposomal formulation of curcumin would suppress the growth of head and neck squamous cell carcinoma (HNSCC) cell lines CAL27 and UM-SCC1 in vitro and in vivo.. HNSCC cell lines were treated with liposomal curcumin at different doses and assayed for in vitro growth suppression using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A reporter gene assay was done on cell lines to study the effect of liposomal curcumin on nuclear factor kappaB (NFkappaB) activation. Western blot analysis was done to determine the effect of curcumin on the expression of NFkappaB, phospho-IkappaBalpha, phospho-AKT (pAKT), phospho-S6 kinase, cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S. Xenograft mouse tumors were grown and treated with intravenous liposomal curcumin. After 5 weeks, tumors were harvested and weighed. Immunohistochemistry and Western blot analyses were used to study the effect of liposomal curcumin on the expression of NFkappaB and pAKT.. The addition of liposomal curcumin resulted in a dose-dependent growth suppression of both cell lines. Liposomal curcumin treatment suppressed the activation of NFkappaB without affecting the expression of pAKT or its downstream target phospho-S6 kinase. Expression of cyclin D1, cyclooxygenase-2, matrix metalloproteinase-9, Bcl-2, Bcl-xL, Mcl-1L, and Mcl-1S were reduced, indicating the effect of curcumin on the NFkappaB pathway. Nude mice xenograft tumors were suppressed after 3.5 weeks of treatment with i.v. liposomal curcumin, and there was no demonstrable toxicity of liposomal curcumin upon autopsy. Immunohistochemistry and Western blot analysis on xenograft tumors showed the inhibition of NFkappaB without affecting the expression of pAKT.. Liposomal curcumin suppresses HNSCC growth in vitro and in vivo. The results suggest that liposomal curcumin is a viable nontoxic therapeutic agent for HNSCC that may work via an AKT-independent pathway.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; Female; Head and Neck Neoplasms; Humans; In Vitro Techniques; Liposomes; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; NF-kappa B; Proto-Oncogene Proteins c-akt

Numerous reports suggest that interleukin-6 (IL-6) promotes survival and proliferation of tumor cells through the phosphorylation of a cell-signaling protein, signal-transducer-and-activator-of-transcription-3 (STAT3). Constitutive activation of STAT3 in head and neck squamous cell carcinoma (HNSCC) and its role in proliferation of this tumor has been demonstrated. Thus, agents that can suppress STAT3 activation have potential for the treatment of HNSCC. In the present report, we demonstrate that most HNSCC cell lines had constitutively active STAT3 and that curcumin (diferuloylmethane), a pharmacologically safe agent in humans, inhibited STAT3 phosphorylation in a dose- and time-dependent manner. Nuclear translocation of STAT3 was also inhibited by curcumin. The inhibition of STAT3 activation by curcumin was reversible, although even 24 hr after curcumin removal, only partial reversal occurred. Besides inhibiting constitutive expression, curcumin also abrogated the IL-6-induced activation of STAT3 in HNSCC cells. When compared with AG490, a well-characterized JAK2 inhibitor, curcumin was more rapid (30 min vs. 4 hr) and more potent (25 microM vs. 100 microM) inhibitor of STAT3 phosphorylation. Curcumin was also a more potent inhibitor of HNSCC cell proliferation than AG490. Overall, our results demonstrated that curcumin is a potent inhibitor of constitutive and IL-6-induced STAT3 phosphorylation. This mechanism may be at least partially responsible for curcumin's ability to suppress proliferation of HNSCC cells.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Curcumin; Head and Neck Neoplasms; Humans; Interleukin-6; Janus Kinase 2; Lymphatic Metastasis; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction; STAT3 Transcription Factor; Tongue Neoplasms; Tyrphostins

The antitumor effect of curcumin (diferuloylmethane) is well established. However, there have been no unbiased studies to identify novel molecular targets of this compound. We therefore undertook a gene expression profiling study to identify novel targets of curcumin. A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated and untreated MDA-1986 cells for differential gene expression. We identified 202 up-regulated mRNAs and 505 transcripts decreased > or =2-fold. The proapoptotic activating transcription factor 3 (ATF3) was induced >4-fold. Two negative regulators of growth control [antagonizer of myc transcriptional activity (Mad) and p27kip1] were induced 68- and 3-fold, respectively. Additionally, two dual-activity phosphatases (CL 100 and MKP-5), which inactivate the c-jun-NH2-kinases, showed augmented expression, coinciding with reduced expression of the upstream activators of c-jun-NH2-kinase (MEKK and MKK4). Of the repressed genes, the expression of Frizzled-1 (Wnt receptor) was most strongly attenuated (8-fold). Additionally, two genes implicated in growth control (K-sam, encoding the keratinocyte growth factor receptor, and HER3) as well as the E2F-5 transcription factor, which regulates genes controlling cell proliferation, also showed down-regulated expression. Considering its role in apoptosis, we determined the contribution of ATF3 to the antitumor effect of curcumin. Curcumin-treated MDA-1986 cells showed a rapid, dose-dependent increase in ATF3/mRNA protein. Moreover, expression of an exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis. Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound.

Topics: Activating Transcription Factor 3; Antineoplastic Agents; Apoptosis; Curcumin; Gene Expression; Gene Expression Profiling; Genetic Vectors; Head and Neck Neoplasms; Humans; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Transcription Factors; Transfection; Tumor Cells, Cultured; Up-Regulation

The purpose of this study was to determine whether curcumin would trigger cell death in the head and neck squamous cell carcinoma (HNSCC) cell lines CCL 23, CAL 27, and UM-SCC1 in a dose-dependent fashion.. HNSCC cells were treated with curcumin and assayed for in vitro growth suppression using 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyl tetrazolium bromide and fluorescence-activated cell sorting analyses. Expression of p16, cyclin D1, phospho-Ikappabeta, and nuclear factor-kappabeta (NF-kappabeta) were measured by Western blotting, gel shift, and immunofluorescence.. Addition of curcumin resulted in a dose-dependent growth inhibition of all three cell lines. Curcumin treatment resulted in reduced nuclear expression of NF-kappabeta. This effect on NF-kappabeta was further reflected in the decreased expression of phospho-Ikappabeta-alpha. Whereas the expression of cyclin D1, an NF-kappabeta-activated protein, was also reduced, there was no difference in the expression of p16 at the initial times after curcumin treatment. In vivo growth studies were done using nude mice xenograft tumors. Curcumin was applied as a noninvasive topical paste to the tumors and inhibition of tumor growth was observed in xenografts from the CAL27 cell line.. Curcumin treatment resulted in suppression of HNSCC growth both in vitro and in vivo. Our data support further investigation into the potential use for curcumin as an adjuvant or chemopreventive agent in head and neck cancer.

Topics: Animals; Annexin A5; Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Nucleus; Cell Separation; Cell Survival; Curcumin; Cyclin D1; Dose-Response Relationship, Drug; Female; Flow Cytometry; Head and Neck Neoplasms; Humans; I-kappa B Proteins; In Vitro Techniques; Mice; Mice, Nude; Microscopy, Fluorescence; Neoplasm Transplantation; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Tetrazolium Salts; Thiazoles

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.

Topics: Animals; Antibodies; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Division; Cell Survival; Curcumin; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; I-kappa B Kinase; Neoplasm Metastasis; NF-kappa B; Protein Serine-Threonine Kinases; Rabbits; Signal Transduction; Tumor Cells, Cultured