stilbenes and Carcinoma--Squamous-Cell

Head and neck squamous cell carcinoma (HNSCC) accounts for around 6% of all cancers in the USA. Few of the greatest obstacles in HNSCC include development of secondary primary tumor, resistance and toxicity associated with the conventional treatments, together decreasing the overall 5-year survival rate in HNSCC patients to ≤50%. Radiation and chemotherapy are the conventional treatment options available for HNSCC patients at both early and late stage of this cancer type malignancy. Unfortunately, patients response poorly to these therapies leading to relapsed cases, which further, emphasizes the need of additional strategies for the prevention/intervention of both primary and the secondary primary tumors post-HNSCC therapy. In recent years, growing interest has focused on the use of natural products or their analogs to reduce the incidence and mortality of cancer, leading to encouraging results. Resveratrol, a component from grape skin, is one of the well-studied agents with a potential role in cancer chemoprevention and other health benefits. As an anticancer agent, resveratrol suppresses metabolic activation of pro-carcinogens to carcinogens by modulating the metabolic enzymes responsible for their activation, and induces phase II enzymes, thus, further detoxifying the effect of pro-carcinogens. Resveratrol also inhibits cell growth and induces cell death in cancer cells by targeting cell survival and cell death regulatory pathways. Growing evidence also suggest that resveratrol directly binds to DNA and RNA, activates antioxidant enzymes, prevents inflammation, and stimulates DNA damage checkpoint kinases affecting genomic integrity more specifically in malignant cells.

Topics: Anticarcinogenic Agents; Carcinoma, Squamous Cell; Chemoprevention; Ethanol; Genetic Predisposition to Disease; Head and Neck Neoplasms; Humans; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes

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 squamous cell carcinoma ranks among the top ten most common cancers worldwide. Despite the success in diagnosis and therapy during the past 30 years, oral squamous cell carcinoma still belongs to the tumor types with a very unfavorable prognosis. In an effort to identify genomic alterations with prognostic relevance, we applied the comparative genomic hybridization technique on oral squamous cell carcinoma. The tumors exhibited from five up to 47 DNA copy number alterations, indicating a considerable degree of genomic imbalance. Out of 35 tumors, 19 showed a gain of chromosome band 7p12. Genomic imbalances were investigated by hierarchical cluster analysis and clustered image mapping to investigate whether genomic profiles correlate with clinical data. Results of the present investigation show that profiling of genomic imbalances in general, and especially of the epidermal growth factor receptor (EGFR) on 7p12, may be suitable as prognostic factors. In order to identify small-molecule inhibitors for EGFR, we established a database of 531 natural compounds derived from medicinal plants used in traditional Chinese medicine. Candidate compounds were identified by correlation analysis using the Kendall tau-test of IC50 values of tumor cell lines and microarray-based EGFR mRNA expression. Further validation was performed by molecular docking studies using the AutoDock program with the crystal structure of EGFR tyrosine kinase domain as docking template. We estimate these results will be a further step toward the ultimate goal of individualized, patient-adapted tumor treatment based on tumor molecular profiling.

Topics: Age Factors; Alcohol Drinking; Antineoplastic Agents; Aporphines; Azo Compounds; Berberine; Carcinoma, Squamous Cell; Chromosome Aberrations; Crystallography, X-Ray; Databases, Factual; DNA, Neoplasm; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; ErbB Receptors; Erlotinib Hydrochloride; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, erbB-1; Humans; Mouth Neoplasms; Neoplasm Proteins; Nucleic Acid Hybridization; Polymorphism, Single Nucleotide; Prognosis; Protein Kinase Inhibitors; Quinazolines; Risk Factors; Smoking; Stilbenes; Structure-Activity Relationship

Topics: Administration, Oral; Administration, Topical; Allyl Compounds; Animals; Anticarcinogenic Agents; Antioxidants; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cocarcinogenesis; Curcumin; Female; Flavonoids; Humans; Male; Mice; Mice, Inbred SENCAR; Neoplasms, Radiation-Induced; Papilloma; Phenols; Phytotherapy; Plants, Medicinal; Polymers; Reactive Oxygen Species; Resveratrol; Silymarin; Skin Neoplasms; Stilbenes; Sulfides; Tea; Ultraviolet Rays; Zingiber officinale

Topics: Animals; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinogens; Carcinoma, Squamous Cell; Child; Ear Neoplasms; Ependymoma; Female; Humans; Immunosuppressive Agents; Isoniazid; Maternal-Fetal Exchange; Mice; Mycotoxins; Neoplasms; Nitrosourea Compounds; Occupational Diseases; Oligodendroglioma; Otorhinolaryngologic Diseases; Pregnancy; Rats; Stilbenes

The vascular disrupting agent combretastatin-A4-phosphate (CA4P) demonstrated antitumour activity in preclinical studies when combined with radiation.. Patients with non-small-cell lung cancer (NSCLC), prostate adenocarcinoma, and squamous cell carcinoma of the head and neck (SCCHN) received 27 Gy in 6 fractions treating twice weekly over 3 weeks, 55 Gy in 20 fractions over 4 weeks, and 66 Gy in 33 fractions over 6 weeks respectively. CA4P was escalated from 50 mg/m2 to 63 mg/m2. CA4P exposure was further increased from one to three to six doses. Patients with SCCHN received cetuximab in addition.. Thirty-nine patients received 121 doses of CA4P. Dose-limiting toxic effects (DLTs) of reversible ataxia and oculomotor nerve palsy occurred in two patients with prostate cancer receiving weekly CA4P at 63 mg/m2. DLT of cardiac ischaemia occurred in two patients with SCCHN at a weekly dose of 50 mg/m2 in combination with cetuximab. Three patients developed grade 3 hypertension. Responses were seen in 7 of 18 patients with NSCLC. At 3 years, 3 of 18 patients with prostate cancer had prostate-specific antigen relapse.. Radiotherapy with CA4P appears well tolerated in most patients. The combination of CA4P, cetuximab, and radiotherapy needs further scrutiny before it can be recommended for clinical studies.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chemoradiotherapy; Dose-Response Relationship, Drug; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Middle Aged; Prostatic Neoplasms; Squamous Cell Carcinoma of Head and Neck; Stilbenes

Cell proliferation and cell death abnormalities are strongly linked to the development of cancer, including lung cancer. The purpose of this study was to investigate the effect of pterostilbene on cell proliferation and cell death via cell cycle arrest during the transition from G1 to S phase and the p53 pathway. A total of 24 female Balb/C mice were randomly categorized into four groups (n = 6): N-nitroso-tris-chloroethyl urea (NTCU) induced SCC of the lungs, vehicle control, low dose of 10 mg/kg PS + NTCU (PS10), and high dose of 50 mg/kg PS + NTCU (PS50). At week 26, all lungs were harvested for immunohistochemistry and Western blotting analysis. Ki-67 expression is significantly lower, while caspase-3 expression is significantly higher in PS10 and PS50 as compared to the NTCU (p < 0.05). There was a significant decrease in cyclin D1 and cyclin E2 protein expression in PS10 and PS50 when compared to the NTCU (p < 0.05). PS50 significantly increased p53, p21, and p27 protein expression when compared to NTCU (p < 0.05). Pterostilbene is a potential chemoprevention agent for lung SCC as it has the ability to upregulate the p53/p21 pathway, causing cell cycle arrest.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Proliferation; Cyclin D1; Cyclins; Disease Models, Animal; Down-Regulation; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Mice, Inbred BALB C; Stilbenes; Tumor Suppressor Protein p53; Up-Regulation

Lung cancer is the leading cause of cancer-related deaths, and squamous cell carcinoma (SCC) is one of the most common types of lung cancer. Chemoprevention of lung cancer has gained increasing popularity as an alternative to treatment in reducing the burden of lung cancer. Pterostilbene (PS) may be developed as a chemopreventive agent due to its pharmacological activities, such as anti-proliferative, anti-inflammatory and antioxidant properties. This study aimed to investigate the effect of PS on the development of lung SCC in the mouse model.. A total of 24 seven-week-old female Balb/C mice were randomly categorised into four groups, including two control groups comprising the N-nitroso-trischloroethylurea (NTCU)-induced lung SCC and vehicle control (VC) groups and two treatment groups comprising the 10mg/kg PS (PS10) and 50mg/kg PS (PS50) groups. All lung organs were harvested at week 26 for histopathological analysis.. All PS treatment groups showed chemopreventive activity by inhibiting the progression of lung SCC formation with PS10, resulting in mild hyperplasia, and PS50 was completely reversed in the normal bronchial epithelium layer compared with the VC group. PS treatment also reduced the expression of cytokeratin 5/6 in the bronchial epithelium layer. Both PS10 and PS50 significantly reduced the epithelium thickness compared to the NTCU group (p<0.05). PS is a potential chemopreventive agent against lung SCC growth by suppressing the progression of pre-malignant lesions and reducing the thickness of the bronchial epithelium.. The underlying molecular mechanisms of PS in lung SCC should be further studied.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Carmustine; Disease Models, Animal; Female; Keratin-15; Keratin-6; Lung; Lung Neoplasms; Mice, Inbred BALB C; Stilbenes

Pinosylvin possesses several biological properties, including anti-inflammatory, antitumor, and antioxidant characteristics. However, the effects of pinosylvin on the migration and invasion of human oral cancer cells and the underlying mechanisms remain unclear.. In this research, we investigated the outcome of different concentrations of pinosylvin (0-80 μM) on the metastatic and invasive abilities of SAS, SCC-9, and HSC-3 cells.. Western blotting assay and Gelatin zymography assay indicated that pinosylvin inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and reduced its protein level but increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). Additionally, the wound healing assay and Transwell method showed that pinosylvin reduced the migration of SAS, SCC-9 and HSC-3 oral cancer cells. Besides, pinosylvin decreased the phosphorylation of ERK1/2 protein experssion in both SAS and SCC-9 cells.. These results indicate that pinosylvin is a potential anticancer agent for preventing oral cancer metastasis.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Mouth Neoplasms; Neoplasm Invasiveness; Phosphorylation; Signal Transduction; Stilbenes; Tissue Inhibitor of Metalloproteinase-2

Squamous cell carcinoma (SCC) is one of the most common skin cancers. Photodynamic therapy (PDT) is a non-invasive treatment for SCC, but it is usually effective only on tumors just under the skin. Resveratrol (Res) is a polyphenolic compound, which is capable of promoting apoptosis of a variety of cancer cells. Res administration is non-invasive and effective on SCC, thus it may be used as an adjuvant for PDT. So far, there is no published study investigating the combination use of PDT with Res to improve clinical outcome of SCC. So in this study, we will examine the effectiveness of combined treatment of PDT and Res as well as its underlying mechanism.. The human HaCaT keratinocytes and human A431 epidermoid carcinoma cells were treated with ALA-PDT or/and Res, and cell proliferation and apoptosis were evaluated by MTT and flow cytometry respectively afterwards. p-ERK, p38, p53 and caspase-3 protein expression was examined by western blot. Then a p38 inhibitor was added to test the involvement of p38 pathway in A431 cells responding to ALA-PDT and Res treatments.. The results showed that Res could enhance the effect of ALA-PDT on cell proliferation and apoptosis in A431 cells. We also found that the expression of p-ERK, p-p38, p53 and caspase-3 was increased. However, inhibition of p38 pathway attenuated the effect of Res.. Our study demonstrated that Res could enhance the effect of ALA-PDT against skin cancer cells through p38/ MAPK pathway.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Humans; MAP Kinase Signaling System; Photochemotherapy; Resveratrol; Skin Neoplasms; Stilbenes

Oral squamous cell carcinoma (OSCC) is one of the most aggressive and deadliest tumors worldwide. The aryl hydrocarbon receptor (AHR) is a nuclear transcription factor known as a dioxin receptor and mediates the toxic effects of industrial contaminants. In addition, AHR has been implicated in multiple cellular processes and its expression has been shown to play a critical role in tumorigenesis, including human oral cancer cell lines. In the present study, we evaluated the expression of AHR/HSP-90 in 25 formalin‑fixed, paraffin-embedded human oral cancer specimens by IHC analysis. CYP1A1 expression was regarded as an AHR reporter gene. The data indicated a complete correlation between AHR expression and cancer grade enabling us to propose AHR as a prognostic marker of oral cancer. Moreover, in OSCC cell line CAL27, we observed the modulatory effect of polydatin, a widespread natural substance and direct precursor of resveratrol, on AHR expression. A computational approach was performed to predict the site of interaction of polydatin on the AHR surface. Our studies confirm the involvement of AHR signaling in the clinicopathological specimens of oral cancer and suggest the use of polydatin for oral cancer prevention.

Topics: Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Carcinoma, Squamous Cell; Case-Control Studies; Cell Proliferation; Cytochrome P-450 CYP1A1; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Glucosides; HSP90 Heat-Shock Proteins; Humans; Male; Middle Aged; Mouth Neoplasms; Neoplasm Grading; Pilot Projects; Receptors, Aryl Hydrocarbon; Stilbenes; Tumor Cells, Cultured

Cancer is the most common cause of death worldwide with approximately one third of people being diagnosed with cancer in their lifetime. Pinostilbene hydrate (PSH) A methylated derivative of resveratrol Has been reported to possess antioxidative Cardioprotective and anticancer properties. However the antimetastatic effect of pinostilbene in oral squamous cell carcinoma (OSCC) remains unknown.. In this study We investigated the effect of PSH on antimetastatic activity and the relevant signaling pathways underlying mechanisms of SCC-9 SAS and HSC-3 oral cancer cell lines by MTT assay Wound healing Transwell assay Zymography and western blot analysis.. Our findings indicated that PSH inhibits migration and invasion ability by reducing the protein activity and expression of matrix metalloproteinases-2 (MMP-2) in all three cell lines. Moreover • The phosphorylation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (p38) had significant inhibitory effects in the presence of PSH in the SCC9 and SAS cell lines. A combination of ERK1/2 and p38 inhibitors with PSH also reduced the migration and activity of MMP-2 in the SCC9 and SAS cell lines.. This study demonstrated that PSH suppresses MMP-2 enzymatic activity by downregulating the p38/ERK1/2 pathway and that it might be a promising agent for preventing OSCC cell metastasis.

Topics: Butadienes; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Humans; Imidazoles; Matrix Metalloproteinase 2; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mouth Neoplasms; Nitriles; p38 Mitogen-Activated Protein Kinases; Pyridines; Signal Transduction; Stilbenes

The present study was performed to investigate the effect of resveratrol (trans-3,4',5-trihydroxystilbene) present as a natural phytoalexin in grapes, peanuts, and red wine on oral squamous cancer cell lines, SCC-VII, SCC-25, and YD-38. MTS assay and flow cytometry, respectively, were used for the analysis of inhibition of cell proliferation and apoptosis. Western blot analysis was performed to examine the effect of resveratrol on the expression of proteins associated with cell cycle regulation. The results revealed a concentration- and time-dependent inhibition of proliferation in all the three tested cell lines on treatment with resveratrol. The IC50 of resveratrol for SCC-VII, SCC-25, and YD-38 cell lines was found to be 0.5, 0.7, and 1.0 μg/ml, respectively, after 48-h treatment. Examination of the cell cycle analysis showed that resveratrol treatment induced cell cycle arrest in the G2/M phase and enhanced the expression of phospho-cdc2 (Tyr 15), cyclin A2, and cyclin B1 in the oral squamous cell carcinoma (OSCC) cells. It also caused a marked increase in the percentage of apoptotic cells as revealed by the fluorescence-activated cell sorting analysis. Thus, resveratrol exhibits inhibitory effect on the proliferation of OSCC oral cancer cells through the induction of apoptosis and G2/M phase cell cycle arrest.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Humans; M Phase Cell Cycle Checkpoints; Mouth Neoplasms; Resveratrol; Stilbenes

The rising incidence of head and neck cancer and the drawbacks of currently used therapeutic strategies such as salvage surgery followed by adjuvant chemo- or radiotherapy have encouraged pursuits for better therapeutic approaches. This work describes the development and characterization of a PEGylated liposomal nanocarrier encapsulated with trans-resveratrol (Res), a plant stilbenoid, and doxorubicin hydrochloride (Dox), a standard chemotherapeutic agent for treatment of oral squamous cell carcinoma. The two drugs were loaded in liposomes prepared from egg phosphatidylcholine and DSPE-PEG with maximum encapsulation efficiencies of about 80% for each drug achieved at Res to Dox ratio of 2:1. The liposomal suspension was found to be stable with a zeta potential of -30.53 mV and size of approximately 250 nm. Thermal properties and release kinetics of the dual drug loaded liposomes were determined. The nanoformulation was evaluated for its in vitro anticancer efficacy on an oral squamous cell carcinoma cell line (NT8e). The cell uptake mechanism of the liposomal formulation was determined using pharmacological inhibitors for different endocytosis pathways. The combination effect of the two drugs was evaluated in free form and was found to have synergistic effects. The formulation was found to have a higher IC50 value than that of free doxorubicin hydrochloride but was found to have a superior effect on the signaling proteins involved in apoptosis and cell cycle.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Doxorubicin; Head and Neck Neoplasms; Humans; Liposomes; Nanoparticles; Resveratrol; Stilbenes

Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division.. Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models.. The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated.. We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells.. We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment.. Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Head and Neck Neoplasms; Humans; Janus Kinase 1; Janus Kinase 2; Phosphorylation; Radiation-Sensitizing Agents; Resveratrol; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; src-Family Kinases; STAT3 Transcription Factor; Stilbenes; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins

Preventive measures against oral carcinogenesis are urgently warranted to lower the high morbidity and mortality associated with this malignancy worldwide. Here, we investigated the chemopreventive efficacy of grape seed extract (GSE) and resveratrol (Res) in 4-nitroquinoline-1-oxide (4NQO)-induced tongue tumorigenesis in C57BL/6 mice. Following 8 weeks of 4NQO exposure (100 µg/ml in drinking water), mice were fed with either control AIN-76A diet or diet containing 0.2% GSE (w/w) or 0.25% Res (w/w) for 8 subsequent weeks, while continued on 4NQO. Upon termination of the study at 16 weeks, tongue tissues were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for molecular targets by immunohistochemistry. GSE and Res feeding for 8 weeks, moderately decreased the incidence, but significantly prevented the multiplicity and severity of 4NQO-induced preneoplastic and neoplastic lesions, without any apparent toxicity. In tongue tissues, both 4NQO + GSE and 4NQO + Res treatment correlated with a decreased proliferation (BrdU labeling index) but increased apoptotic death (TUNEL-positive cells) as compared to the 4NQO group. Furthermore, tongue tissues from both the 4NQO + GSE and 4NQO + Res groups showed an increase in activated metabolic regulator phospho-AMPK (Thr172) and decreased autophagy flux marker p62. Together, these findings suggest that GSE and Res could effectively prevent 4NQO-induced oral tumorigenesis through modulating AMPK activation, and thereby, inhibiting proliferation and inducing apoptosis and autophagy, as mechanisms of their efficacy.

Topics: 4-Nitroquinoline-1-oxide; AMP-Activated Protein Kinases; Animals; Anticarcinogenic Agents; Apoptosis; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Female; Grape Seed Extract; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL; Resveratrol; Stilbenes; Tongue; Tongue Neoplasms

Naturally occurring agents, such as resveratrol, have been determined to benefit health. Numerous studies have demonstrated that resveratrol has antioxidative, cardioprotective, and neuroprotective properties. However, the effect of resveratrol exerts on the metastasis of oral cancer cells remains unclear. In this study, we investigated the effect the anti-invasive activity of resveratrol on a human oral cancer cell line (SCC-9) in vitro and the underlying mechanisms.. Cell viability was examined by MTT assay, whereas cell motility was measured by migration and wound-healing assays. Zymography, reverse-transcriptase polymerase chain reaction (PCR), and promoter assays confirmed the inhibitory effects of resveratrol on matrix metalloproteinase-9 (MMP-9) expression in oral cancer cells.. We established that various concentrations (0-100 μM) of resveratrol inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced migration capacities of SCC-9 cells and caused no cytotoxic effects. Zymography and Western blot analyses suggested that resveratrol inhibited TPA-induced MMP-9 gelatinolytic activity and protein expression. In addition, the results indicated that resveratrol inhibited the phosphorylation of c-Jun N-terminal kinase (JNK)1/2 and extracellular-signal-regulated kinase (ERK)1/2 involved in downregulating protein expression and the transcription of MMP-9.. In summary, resveratrol inhibited MMP-9 expression and oral cancer cell metastasis by downregulating JNK1/2 and ERK1/2 signals pathways and, thus, exerts beneficial effects in chemoprevention.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Down-Regulation; Enzyme Activation; Head and Neck Neoplasms; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Resveratrol; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Stilbenes; Tetradecanoylphorbol Acetate; Tongue Neoplasms

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

To study the radiosensitizing effect of resveratrol on hypopharyngeal carcinoma cell line FADU in vitro.. Hypopharyngeal carcinoma cell line FADU was cultured in in vitro DMEM. Its inhibition on cell proliferation was detected using cytotoxicity test (MTT assay). The cell survival curve was drawn using clone formation to obtain sensitive enhancement ratio (SER). Changes of the cell cycle and cell apoptosis were analyzed using flow cytometry (FCM).. Results of MTT showed the inhibition of resveratrol on FADU cells increased along with its concentrations (P < 0.05). Results of clone formation indicated the surviving fraction at 2 Gy (SF2) was 0.717 ± 0.062 in the irradiation group, and 0.426 ± 0.035 in the resveratrol plus irradiation group (with SER ranged 1.684 ± 0.178) with statistical difference (P = 0.007). Results of FCM showed that after radiation of 4 Gy radiation, cells at G2/M phase arrest increased, but cells at G1 decreased. After radiation of resveratrol for 24 h, cells at G1 decreased, but cells at G2/M phase and S phase arrest increased. When 4 Gy radiation combined resveratrol was used, cells at G2/M phase arrest significantly increased, but cells at G1 significantly decreased. The apoptosis rate was 1.94% ± 1.65% in the control group, 4.56% ± 0.92% in the irradiation group, 2.03% ± 1.46% in the resveratrol group, and 23.11% ± 7.22% in the resveratrol plus irradiation group. There was statistical difference between the resveratrol plus irradiation group and the rest 3 groups (P < 0.05).. Resveratrol could enhance the radiosensitivity of hypopharyngeal carcinoma FADU cells in vitro possibly by inducing cell apoptosis and causing changes in the cell cycle distribution.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Head and Neck Neoplasms; Humans; Hypopharyngeal Neoplasms; Radiation Tolerance; Radiation-Sensitizing Agents; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes

Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated.. MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation.. PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct.. Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Proliferation; Cell Survival; Cyclin D1; Female; Gene Expression; HeLa Cells; Humans; Inhibitor of Apoptosis Proteins; Molecular Chaperones; Phosphorylation; Protein Inhibitors of Activated STAT; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins c-myc; Resveratrol; RNA, Neoplasm; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Survivin; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor A

Autophagy and endoplasmic reticulum (ER) stress response is important for cancer cells to maintain malignancy and resistance to therapy. trans-Resveratrol (RSV), a non-flavonoid agent, has been shown to induce apoptosis in human nasopharyngeal carcinoma (NPC) cells. In this study, the involvements of tumor-specific ER stress and autophagy in the RSV-mediated apoptosis were investigated. In addition to traditional autophagosomes, the images of transmission electron microscopy (TEM) indicated that RSV markedly induced larger, crescent-shaped vacuoles with single-layered membranes whose the expanded cisternae contains multi-lamellar membrane structures. Prolonged exposure to RSV induced a massive accumulation of ER expansion. Using an EGFP-LC3B transfection and confocal laser microscopy approach, we found RSV-induced EGFP-LC3 puncta co-localized with ER-tracker red dye, implicating the involvement of LC3II in ER expansion. The proapoptotic effect of RSV was enhanced after suppression of autophagy by ATG7 siRNA or blocking the autophagic flux by bafilomycin A1, but that was not changed after targeted silence of IRE1 or CHOP by siRNA. Using caspase inhibitors, we demonstrated the upregulation of caspase-12 (casp12) and the activation of casp4 were associated with the proapoptotic induction of RSV through the caspase-9/caspase-3 pathway. Intriguingly, siRNA knockdown of casp12, but not caspase-4, decreased the susceptibility of the NPC cells to RSV-mediated apoptosis. Further, we showed that RSV dose-dependently increased the ceramide accumulation as assessed by LC-MS/MS system. Using serine palmitoyltransferase (SPT, a key enzyme of de novo ceramide biosynthesis) inhibitors (L-cycloserine and myriocin), we found the increased ceramide accumulation was strongly correlated with the proapoptotic potential of RSV. This study revealed the ER expansion and upregulation of ER casp12 together may indicate profound biological effects of RSV and contributed to NPC cell death. Targeting the different status of ER stress may provide a possible strategy for cancer treatments.

Topics: Anticarcinogenic Agents; Apoptosis; Autophagy; Carcinoma, Squamous Cell; Caspase 12; Caspases; Caspases, Initiator; Cell Line, Tumor; Ceramides; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Nasopharyngeal Neoplasms; Resveratrol; Stilbenes

Resveratrol has been reported to exhibit anti-cancer activity. The aim of this study was to examine the effects of resveratrol on the adhesion, migration, and invasion of the oral squamous cell carcinoma (OSCC) cell line KB cell in vitro.. The effect of resveratrol on KB cell adhesion was evaluated by a MTT colorimetric assay, whereas its effects on cell migration and invasion were assessed by a Transwell assay.. The MTT assay revealed that the adhesion of KB cells treated with 100 μmol resveratrol for 1 or 2 h was decreased by 49.92 and 58.21%, respectively (P < 0.05). In the Transwell assay, the migratory and invasive abilities of KB cells treated with 100 μmol resveratrol were decreased by 43.98 and 37.69%, respectively.. Resveratrol inhibited the adhesion, migration, and invasion of OSCC cells in vitro, suggesting that it might serve as a chemopreventive agent for reducing the invasion and metastasis of OSCC.

Topics: Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Colorimetry; Humans; Mouth Neoplasms; Neoplasm Invasiveness; Resveratrol; Stilbenes

To evaluate the effects of resveratrol and irradiation on oral squamous cell carcinoma (OSCC).. Resveratrol was administered at doses of 5, 10, 25, 50 and 100 µM to PE/CA-PJ15 (OSCC) cultures irradiated with different doses (1, 2.5 and 5 Gy). Effects upon cell viability, apoptosis and migration were evaluated after 24, 48 and 72 h incubation.. After 72 h of incubation, the 100 µM dose of resveratrol induced the greatest decrease in cell viability at all irradiation doses. After 24, 48 and 72 h of incubation, 100 µM of resveratrol induced the greatest cell apoptosis at all irradiation doses. The greatest alterations in the distribution of the G0-G1, G2-M and S phases of the cell cycle were recorded with 50 and 100 µM of resveratrol; after 24, 48 and 72 h of incubation, both these doses resulted in an increase in the S phase, at the expense of the G0-G1 and G2-M phases.. Resveratrol increases cytotoxic activity in the PE/CA-PJ15 cell line and reduces cell migration capacity, while the combination of resveratrol and irradiation exerts a synergic effect.

Topics: Anticarcinogenic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Mouth Neoplasms; Radiotherapy Dosage; Resveratrol; S Phase; Stilbenes; Time Factors

Polyphenol compounds, present in a wide variety of natural plants, exhibit antioxidant and free radical scavenging ability and induce apoptosis in various cancer cells. However, the effect of pterostilbene on oral cancer cell metastasis has not been clarified.. The present study aimed to examine the anti-metastatic properties of pterostilbene in human oral squamous cell carcinoma (SCC)-9 cells.. In this study, pterostilbene treatment significantly inhibited migration/invasion capacities of SCC-9 cells in vitro. The results of zymography and western blotting revealed that the activities and protein levels of the MMP-2 and urokinase-type plasminogen activator (u-PA) was inhibited by pterostilbene. Western blot analysis also showed that pterostilbene inhibits the phosphorylation of Akt, extracellular signal-regulated kinase 1/2 and p38. Determinations of the mRNA levels, real-time polymerase chain reaction and promoter assays were conducted to evaluate the inhibitory effects of pterostilbene on MMP-2 and u-PA expression in SCC-9 cells. Such inhibitory effects were associated with the upregulation of tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1 and the downregulation of the transcription factors of NF-κB, SP-1 and CREB signaling pathways.. Pterostilbene may have potential use as a chemopreventive agent against oral cancer metastasis.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; RNA, Messenger; Stilbenes; Up-Regulation; Urokinase-Type Plasminogen Activator

Increasing consumption of tobacco and alcohol has led to a steady increase in the incidence of head and neck cancers in Asia. The drawbacks associated with the existing chemotherapeutic and surgical interventions have necessitated the development of a safer alternative for therapy of head and neck cancers. In this study we have explored the synergistic therapeutic potential of a phytochemical and chemotherapeutic agent using PEGylated liposomes as a delivery vehicle. Resveratrol and 5-fluorouracil were successfully coencapsulated in a single PEGylated nanoliposome. The thermal analysis and the nuclear magnetic resonance results revealed that resveratrol localized near the glycerol backbone of the liposomal membrane while 5-fluorouracil localized closer to the phosphate moiety, which influenced the release kinetics of both drugs. The nanoformulation was tested in vitro on a head and neck cancer cell line NT8e and was found to exhibit a GI50 similar to that of free 5-fluorouracil. Further, gene expression studies showed that the combination of resveratrol and 5-fluorouracil exhibited different effects on different genes that may influence the net antagonistic effect. The coencapsulation of resveratrol and 5-fluorouracil in a liposomal nanocarrier improved the cytotoxicity in comparison with the free drug combination when tested in vitro.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Fluorouracil; Head and Neck Neoplasms; Humans; Liposomes; Nanoparticles; Polyethylene Glycols; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes

Resveratrol shows a growth inhibitory effect in head and neck squamous cell carcinoma (HNSCC) cell lines and acts synergistically in combination with etoposide in three cell lines via the induction of apoptotic and necrotic cell death.. In patients with recurrent/distant HNSCC, one of the limited treatment options is etoposide. The aim of this study was to investigate whether resveratrol is able to enhance the antiproliferative effect of etoposide in vitro synergistically.. Dose-response curves of etoposide and resveratrol in three HNSCC cell lines were generated. Drug combinations in a fixed dose ratio were carried out and results were analyzed by the combination index method. Detection of apoptotic cells was performed by flow cytometry.. Both compounds show a dose- and time-dependent growth inhibitory effect as single agents after treatment. In combination experiments we observed distinct synergistic effects increasing over time in all three cell lines.

Topics: Analysis of Variance; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Etoposide; Flow Cytometry; Head and Neck Neoplasms; Humans; Reference Values; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes

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

Dietary lignans, quercetin and resveratrol have oestrogenic properties, and animal studies suggest that they synergistically decrease cancer risk. A protective effect of lignans on the development of oesophageal cancer in humans has recently been demonstrated, and the present study aimed to test whether these three phytochemicals synergistically decrease the risk of oesophageal cancer. Data from a Swedish nationwide population-based case-control study that recruited 181 cases of oesophageal adenocarcinoma (OAC), 158 cases of oesophageal squamous-cell carcinoma (OSCC), 255 cases of gastro-oesophageal junctional adenocarcinoma (JAC) and 806 controls were analysed. Exposure data were collected through face-to-face interviews and questionnaires. The intake of lignans, quercetin and resveratrol was assessed using a sixty-three-item FFQ. Reduced-rank regression was used to assess a dietary pattern, and a simplified dietary pattern score was categorised into quintiles on the basis of the distribution among the control subjects. Unconditional multivariable logistic regression provided OR with 95% CI, adjusted for all the potential risk factors. A dietary pattern rich in lignans, quercetin and resveratrol was mainly characterised by a high intake of tea, wine, lettuce, mixed vegetables, tomatoes, and whole-grain bread and a low intake of milk. There were dose-dependent associations between simplified dietary pattern scores and all types of oesophageal cancer (all P for trend < 0.05). On comparing the highest quintiles with the lowest, the adjusted OR were found to be 0.24 (95% CI 0.12, 0.49) for OAC, 0.31 (95% CI 0.15, 0.65) for OSCC, and 0.49 (95% CI 0.28, 0.84) for JAC. The results of the present study indicate that a dietary pattern characterised by the intake of lignans, quercetin and resveratrol may play a protective role in the development of oesophageal cancer in the Swedish population.

Topics: Adenocarcinoma; Aged; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Case-Control Studies; Diet; Esophageal Neoplasms; Esophagus; Feeding Behavior; Female; Humans; Lignans; Logistic Models; Male; Middle Aged; Odds Ratio; Plant Extracts; Quercetin; Resveratrol; Stilbenes

To study the radiosensitizing effect of resveratrol on human hypo pharyngeal squamous cell carcinoma (FaDu) cells in nude mice.. Forty-three nude mice bearing FaDu cell xenografts were randomized into control group, radiotherapy (12 Gy) group, resveratrol treatment (50 mg/kg) group, and radiotherapy plus resveratrol treatment group. After corresponding treatments, the tumor volume in the mice was measured every 3 days, and the microvessel density (MVD) in the tumor was evaluated with CD31 immunofluorescence histochemical staining.. The tumor volume and weight were the smallest in mice receiving radiotherapy plus resveratrol treatment (P<0.05) but comparable between those having resveratrol treatment alone and the control mice. Radiotherapy plus resveratrol treatment resulted in a tumor inhibition rate of 76.64% and a significantly decreased MVD in the tumor compared with the other 3 groups.. Resveratrol can produce a radiosensitizing effect on human hypopharyngeal carcinoma in nude mice.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Head and Neck Neoplasms; Humans; Hypopharyngeal Neoplasms; Mice; Mice, Nude; Radiation Tolerance; Radiation-Sensitizing Agents; Resveratrol; Squamous Cell Carcinoma of Head and Neck; Stilbenes; Transplantation, Heterologous; Tumor Burden

Squamous cell carcinoma (SCC) is one of the commonest dermatological malignancies. Resveratrol (Res) is one type of polyphenolic compound which was first identified from the roots of Veratrum grandinorum in 1940. The previous studies found that Res can promote apoptosis of a variety of tumor cell, especially SCC cells. However it is rare to study the inhibition mechanism of Res in the animal model. In this study, through the establishment of human cutaneous SCC A431 xenografts in nude mice, we observed Res inhibition effect and investigated the inhibition mechanism by checking the expression of apoptosis-related factors, p53, ERK and survivin. The results showed that the xenograft volume and weight of Res groups were less than those of the control groups (P<0.05), but the net body mass of nude mice of Res groups was not significantly different from the control groups (P>0.05). The apoptotic index of Res groups were significantly higher than the control groups (P<0.05). The protein and mRNA expression of p53 and ERK were statistically positively correlated (P<0.05) and significantly increased in Res high- and medium-dose groups compared with the control groups (P<0.05). Moreover, the protein and mRNA expression of SVV were negatively correlated with p53 (P<0.05) and lower than the control groups (P<0.05). The results demonstrate Res inhibitory effect and indicate that the inhibition mechanism of Res is to upgrade the protein and mRNA expression of p53 and to downgrade the protein and mRNA expression of SVV, thus inducing the apoptosis of tumor cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Body Weight; Carcinoma, Squamous Cell; Cell Line, Tumor; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Humans; Inhibitor of Apoptosis Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Plant Extracts; Repressor Proteins; Resveratrol; RNA, Messenger; Skin Neoplasms; Stilbenes; Survivin; Transplantation, Heterologous; Tumor Suppressor Protein p53; Veratrum

The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.

Topics: Apoptosis; Autophagy; Carcinoma, Squamous Cell; Cell Line, Tumor; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; K562 Cells; Microscopy, Electron, Transmission; Resveratrol; Stilbenes

Vesicants are potent blistering agents. The prototype vesicant is sulphur mustard gas, first used in World War I, which still has no effective antidote. We used a mustard gas surrogate 2-chloroethyl ethyl sulphide (CEES) to study the ability of resveratrol (RES) and pterostilbene (PTS), two well-established stilbene antioxidants, ebselen (EB-1), an organoselenium compound, and three EB-1 analogues (EB-2, EB-3, and EB-4) to reduce CEES toxicity in human epidermoid carcinoma cells (A-431). Following a 24-hour incubation of a toxic concentration of CEES (1000 μmol L-1), we used the MTT [3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide] test to analyse cell viability. Different concentrations of test antioxidants alone (15 μmol L-1, 30 μmol L-1 or 60 μmol L-1) did not decrease cell viability. Treatment with CEES and test antioxidants for 24 h showed that only EB-1 and its analogues EB-2, EB-3, and EB-4 but not the stilbene compounds could rescue the cells from death. EB-1 and EB-4 were the most effective at reducing CEES cytotoxicity and did so in a concentration-dependent manner, while EB-2 and EB-3 demonstrated the least protective effect. In summary, the data described herein indicate that organoselenium antioxidants, especially EB-4, may prove useful as countermeasures to blistering agents.

Topics: Antioxidants; Azoles; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Chemical Warfare Agents; Humans; Isoindoles; Mustard Gas; Organoselenium Compounds; Oxidative Stress; Protective Agents; Resveratrol; Stilbenes

To explore the anti-tumor effects of resveratrol (Res) upon human skin squamous cell carcinoma A431 xenograft in nude mice and elucidate the regulatory mechanisms of survivin and caspase-3.. The model of human skin squamous cell carcinoma (A431) xenograft in nude mice was established. And the animals were randomly divided into saline-negative control, cyclophosphamide (CTX) positive control, Res high-, medium- and low-dosage and blank control groups (n = 10 each). After drug intervention, tumor-bearing mice were sacrificed. The tumor growth curve was plotted and the Res inhibition rate calculated by terminal tumor weight. The morphological changes of tumor cell among groups were observed by hematoxylin and eosin staining; cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL; the impact of Res upon the protein expressions of survivin and caspase-3 in tumor issues was observed by Western blot. Analysis of variance and Pearson's correlation were employed for statistical analyses.. (1) By the end of treatment, the tumor volume of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups were (1154 ± 255), (1002 ± 115), (1207 ± 176), (1342 ± 211), (1642 ± 226), (1564 ± 156) mm(3) respectively, and tumor weight of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups (1.84 ± 0.30), (1.72 ± 0.39), (1.96 ± 0.40), (2.67 ± 0.73), (3.16 ± 0.52), (3.33 ± 0.59) g respectively. Through analysis of variance, the tumor volume and weight of Res high-, medium-, low-dosage groups were smaller than those of saline-negative control and blank control groups (all P < 0.05). The inhibition rate of Res high-, medium- and low-dosage groups were 45.57%, 37.97% and 15.51% respectively. (2) The apoptosis index of the above groups were 36.79% ± 8.86%, 33.15% ± 6.00%, 18.09% ± 3.92%, 10.53% ± 4.20%, 3.87% ± 1.63%, 2.73% ± 1.61%. Through analysis of variance, the apoptosis index of Res groups were higher than those of saline-negative control and blank control groups (all P < 0.05). (3) The protein expression of survivin/β-actin of each group were 0.48 ± 0.20, 0.19 ± 0.11, 0.22 ± 0.12, 0.28 ± 0.24, 0.98 ± 0.41, 0.85 ± 0.34. The protein expression of caspase-3/β-actin of each group were 0.42 ± 0.09, 0.31 ± 0.10, 0.31 ± 0.07, 0.22 ± 0.08, 0.14 ± 0.04, 0.13 ± 0.05 respectively. Through analysis of variance, the protein expression of survivin of Res groups was lower than those of the saline-negative control and blank control groups (all P < 0.05). And the protein expression of caspase-3 of Res groups were higher than those of the saline-negative control and blank control group (all P < 0.05). Through Pearson's analysis, the protein expression of survivin and caspase-3 had no correlation (r = -0.279, P > 0.05).. Res inhibits the growth of human skin squamous cell carcinoma A431 xenograft in nude mice. And its mechanism may be associated with the apoptosis of tumor cell through the depression of survivin and the activation of caspase-3.

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Caspase 3; Cell Line, Tumor; Female; Humans; Inhibitor of Apoptosis Proteins; Mice; Mice, Nude; Resveratrol; Skin Neoplasms; Stilbenes; Survivin; Xenograft Model Antitumor Assays

Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, might possess anti-cancer properties. We aimed to evaluate the efficacy of Riccardin D-26 as a candidate compound for treatment of cancers with sensitive or drug resistant cells.. Experiments were performed on human oral squamous carcinoma KB cells and vincristin-selected MDR KB/VCR cells. The inhibition of cell growth was evaluated by colorimetric and clonogenic assays. The apoptotic cells were determined by the Annexin V-FITC/PI staining assay. JC-1 fluorescence probe was used to examine the mitochondria membrane potential (MMP). Further experiments were performed in nude mice bearing KB or KB/VCR xenografts. Riccardin D-26 was administered by injection for 2weeks. The specimens of KB and KB/VCR xenografts were removed for TUNEL staining and Western blotting analysis.. Riccardin D-26 significantly inhibited cancer growth in both KB and KB/VCR cells. Riccardin D-26's activity in cancer cells was greater than that in human normal liver cells. In mice, Riccardin D-26 effectively prevented the growth of KB and KB/VCR xenografts without significant toxicity. Further studies suggested that Riccardin D-26 inhibited cancer growth by inducing apoptosis in the activation of mitochondria-mediated intrinsic apoptosis pathway. Riccardin D-26 also possessed this activity in regulation of mitogen-related protein kinases such as MAPK and PI3K/Akt, which is associated with its inhibitory effect on KB/VCR cells.. Riccardin D-26 possessed an anti-proliferation activity against both sensitive KB and MDR KB/VCR cancer cells.. Riccardin D-26 could be a promising agent for treatment of cancers with sensitive or drug resistant cells.

Topics: Animals; Annexin A5; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Humans; Macrocyclic Compounds; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; Mitochondrial Membranes; Mouth Neoplasms; Phenyl Ethers; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Stilbenes; Xenograft Model Antitumor Assays

Resveratrol (RES) is a potent anti-cancer agent. We have previously reported that RES arrests the growth of invasive human A431 squamous cell carcinoma (SCC) cells. In this study, we show that oral administration of RES to highly tumor-susceptible p53(+/-)/SKH-1 mice markedly delayed UV-induced skin tumorigenesis and reduced the malignant conversion of benign papillomas to SCCs. Transforming growth factor-β2 (TGF-β2) was predominantly overexpressed in UV-induced SCCs and its expression was diminished in RES-treated SCCs/skin. In addition to the inhibition of TGF-β2 expression, RES increased the level of epithelial cadherin. This RES-mediated TGF-β2 downregulation led to the inhibition of both TGF-β2/Smad-dependent and -independent pathways, and suppressed the invasiveness of A431 cells. Addition of TGF-β2, but not TGF-β1, rescued the RES-mediated downregulation of p-extracellular signal-regulated kinases 1/2, p-Smad3, and α-smooth muscle actin. The protein kinase B (Akt) substrate cAMP response-binding protein (pCREB) transcription factor is known to regulate TGF-β2 expression, and RES treatment decreased phosphorylation of Akt and pCREB. Expression of constitutively active Akt blocked RES inhibition of CREB and TGF-β2, and rescued RES inhibition of cellular invasiveness. Our data indicate that RES suppresses UV-induced malignant tumor progression in p53(+/-)/SKH-1 mice and that RES-inhibited invasiveness of human A431 SCC cells appears to occur, in part, through the Akt-mediated downregulation of TGF-β2.

Topics: Animals; Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Down-Regulation; Female; Humans; Male; Mice; Mice, Hairless; Mice, Inbred C57BL; Mice, Mutant Strains; Resveratrol; Signal Transduction; Skin Neoplasms; Stilbenes; Transforming Growth Factor beta2; Tumor Suppressor Protein p53; Ultraviolet Rays

Alterations in Smad4 signaling and its loss cause genomic instability and head and neck squamous cell carcinoma (HNSCC), suggesting that agents that target both Smad4-dependent and -independent pathways could control HNSCC.. Resveratrol efficacy was evaluated against the HNSCC cells FaDu, Cal27, Det562, and Cal27-Smad4 for viability, DNA damage, cell-cycle progression, and apoptosis, as well as γ-H2AX expression, and focus formation (γ-H2AX and Brca1). Resveratrol efficacy was also examined in nude mice for FaDu xenograft growth. Xenografts were analyzed for γ-H2AX and cleaved caspase-3.. Resveratrol (5-50 μmol/L) suppressed viability and induced DNA damage in FaDu and Cal27 cells but not in normal human epidermal keratinocytes and human foreskin fibroblasts, showing its selectivity toward HNSCC cells; however, Det562 cells were resistant to resveratrol even at 100 μmol/L. Cal27 cells stably transfected with Smad4 showed similar resveratrol effects as parental Cal27, indicating that a lack of resveratrol effect in Det562 cells was independent of Smad4 status in these cells. Furthermore, resveratrol caused S-phase arrest and apoptotic death of FaDu and Cal27 cells together with induction of Brca1 and γ-H2AX foci. Resveratrol (50 mg/kg body weight) treatment also inhibited FaDu tumor growth in nude mice, and γ-H2AX and cleaved caspase-3 were strongly increased in xenografts from resveratrol-treated mice compared with controls.. Our findings for the first time showed antiproliferative, DNA damaging, and apoptotic effects of resveratrol in HNSCC cells independent of Smad4 status, both in vitro and in vivo, suggesting that more studies are needed to establish its potential usefulness against HNSCC.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; BRCA1 Protein; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Survival; Cells, Cultured; Comet Assay; DNA Damage; Head and Neck Neoplasms; Histones; Humans; Immunoblotting; Immunohistochemistry; Male; Mice; Mice, Nude; Mutation; Resveratrol; Smad4 Protein; Stilbenes; Transfection; Xenograft Model Antitumor Assays

Oral squamous cell carcinoma (OSCC) develops slowly and it is usually preceded by identifiable oral preneoplastic lesions (OPLs): chemoprevention could be a promising approach. Resveratrol (RV) is a plant-based agent characterized by a strong in vitro antineoplastic action, but this effect has not been clinically confirmed owing to its metabolic inactivation. In order to circumvent this limitation and to improve RV efficacy, it was locally applied and complexed with a protective and solubilising vehicle (2-hydroxypropyl-beta-cyclodextrin, HPbetaCD). The experimentation was performed in vitro on 7,12-dimethylbenz[a]anthracene-induced hamster OSCC cell line (HCPC I) and in vivo in the related animal model, by comparison of two RV-HPbetaCD formulations (cream and mouthwash) and RV alone. Vehicles and RV-formulations were free from toxicity. Antiproliferative action of RV on HCPC I was concentration- and time-dependent, and was improved in HPbetaCD-formulations. In vivo, RV prevented OPL and OSCC appearance and growth. Here, too, HPbetaCD-formulations (mainly mouthwash) demonstrated the best chemopreventive effects in terms of lesions prevalence, multiplicity, dimension, and histological signs of malignancy. HPLC detection of RV corroborated that its action is concentration-correlated and is improved by its inclusion in HPbetaCDs. In summary, our study demonstrates that RV is effective in the chemoprevention of DMBA-induced oral carcinogenesis and when it is complexed with HPbetaCDs its efficacy is significantly improved.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anticarcinogenic Agents; beta-Cyclodextrins; Carcinogens; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Transformation, Neoplastic; Cheek; Cricetinae; Drug Combinations; Mesocricetus; Mouth Neoplasms; Pharmaceutical Vehicles; Resveratrol; Stilbenes

Resveratrol has been reported to suppress cancer progression in several in vivo and in vitro models, whereas ultraviolet B (UVB), a major risk for skin cancer, is known to induce cell death in cancerous cells. Here, we investigated whether resveratrol can sensitize A431 human epidermoid carcinoma cells to UVB-induced cell death. We examined the combined effect of UVB (30 mJ/cm(2)) and resveratrol (60 microM) on A431 cells. Exposure of A431 carcinoma cells to UVB radiation or resveratrol can inhibit cell proliferation and induce apoptosis. However, the combination of resveratrol and UVB exposure was associated with increased proliferation inhibition of A431 cells compared with either agent alone. Furthermore, results showed that resveratrol and UVB treatment of A431 cells disrupted the nuclear factor-kappaB (NF-kappaB) pathway by blocking phosphorylation of serine 536 and inactivating NF-kappaB and subsequent degradation of IkappaBalpha, which regulates the expression of survivin. Resveratrol and UVB treatment also decreased the phosphorylation of tyrosine 701 of the important transcription factor signal transducer activator of transcription (STAT1), which in turn inhibited translocation of phospho-STAT1 to the nucleus. Moreover, resveratrol/UVB also inhibited the metastatic protein LIMK1, which reduced the motility of A431 cells. In conclusion, our study demonstrates that the combination of resveratrol and UVB act synergistically against skin cancer cells. Thus, resveratrol is a potential chemotherapeutic agent against skin carcinogenesis.

Topics: Antioxidants; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Humans; Inhibitor of Apoptosis Proteins; Lim Kinases; Microtubule-Associated Proteins; NF-kappa B; Phosphorylation; Radiation-Sensitizing Agents; Resveratrol; Skin Neoplasms; Stilbenes; Survivin; Ultraviolet Rays

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin present mainly in grapes, red wine and berries, is known to possess strong chemopreventive and anticancer properties. Here, we demonstrated the anti-proliferative and apoptosis-inducing activities of resveratrol in human epidermoid carcinoma A431 cells. Resveratrol has cytotoxic effects through inhibiting cellular proliferation of A431 cells, which leads to the induction of apoptosis, as evident by an increase in the fraction of cells in the sub-G(1) phase of the cell cycle and Annexin-V binding of externalized phosphatidylserine. Results revealed that inhibition of proliferation is associated with regulation of the JAK/STAT pathway, where resveratrol prevents phosphorylation of JAK, thereby inhibiting STAT1 phosphorylation. Furthermore, resveratrol treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. Consequently, an imbalance in the Bax/Bcl-2 ratio triggered the caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favor of apoptosis. These observations indicate that resveratrol treatment inhibits JAK/STAT-mediated gene transcription and induce the mitochondrial cell death pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Squamous Cell; Caspases; Cell Line, Tumor; Humans; Janus Kinases; Membrane Potential, Mitochondrial; Phosphorylation; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Resveratrol; STAT1 Transcription Factor; Stilbenes; Transcription, Genetic

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in grapes, and has been shown to inhibit the growth of various types of cancer cells. We investigated the mechanism of the antiproliferative effect of resveratrol in A431-transformed keratinocytes harbouring mutant p53, and show that it is accompanied by G1 cell cycle arrest, which coincides with a marked inhibition of G1 cell cycle regulatory proteins, including cyclins A and D1 and cyclin-dependent kinase (CDK)6 and p53-independent induction of p21WAF1. Cell cycle arrest was also associated with the accumulation of hypophosphorylated Rb and p27KIP1. Resveratrol inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 > extracellular signal-regulated protein kinase (ERK)1/2 signalling, downregulated c-Jun, and suppressed activating protein (AP)-1 DNA-binding and promoter activity. In addition, the inhibition of MEK1 > ERK1/2 signalling appears to be independent of retinoblastoma protein (pRb) hypophosphorylation in A431 cells, as PD098059 did not suppress pRb phosphorylation. Our results demonstrate that resveratrol affects multiple cellular targets in A431 cells, and that the downregulation of both AP-1 and pRb contributes to its antiproliferative activity in these cells.

Topics: Antineoplastic Agents, Phytogenic; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dimerization; DNA-Binding Proteins; Dose-Response Relationship, Drug; Flavonoids; Gene Expression; Humans; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-jun; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; Transcription Factor AP-1

Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1alpha protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Stilbenes; Tongue Neoplasms; Transcriptional Activation; Vascular Endothelial Growth Factors

Resveratrol (trans-3,4',5,-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with cancer-preventive properties. The mechanism by which resveratrol imparts cancer chemopreventive effects is not clearly defined. Here, we demonstrate that resveratrol, via modulations in cyclin-dependent kinase (cdk) inhibitor-cyclin-cdk machinery, results in a G(1)-phase arrest of the cell cycle followed by apoptosis of human epidermoid carcinoma (A431) cells. Resveratrol treatment (1-50 microM for 24 h) of A431 cells resulted in a dose-dependent (a) inhibition of cell growth as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, (b) G(1)-phase arrest of the cell cycle as shown by DNA cell cycle analysis, and (c) induction of apoptosis as assessed by ELISA. The immunoblot analysis revealed that resveratrol treatment causes a dose- and time-dependent (a) induction of WAF1/p21; (b) decrease in the protein expressions of cyclin D1, cyclin D2, and cyclin E; and (c) decrease in the protein expressions of cdk2, cdk4, and cdk6. Resveratrol treatment was also found to result in a dose- and time-dependent decrease in kinase activities associated with all of the cdks examined. Taken together, our study suggests that resveratrol treatment of the cells causes an induction of WAF1/p21 that inhibits cyclin D1/D2-cdk6, cyclin D1/D2-cdk4, and cyclin E-cdk2 complexes, thereby imposing an artificial checkpoint at the G(1)-->S transition of the cell cycle. This series of events results in a G(1)-phase arrest of the cell cycle, which is an irreversible process that ultimately results in the apoptotic death of cancer cells. To our knowledge, this is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of cancer cells by resveratrol.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Squamous Cell; CDC2-CDC28 Kinases; Cell Division; Cyclin D1; Cyclin D2; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases; Cyclins; G1 Phase; Humans; Phosphotransferases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Resveratrol; Stilbenes; Tumor Cells, Cultured

Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC).. Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease.. In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model.. In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Transplantation; Prodrugs; Stilbenes; Tumor Cells, Cultured

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, nuts, many other fruits, and red wine, is a potent antioxidant with anti-inflammatory and cancer-preventive properties. The mechanism(s) by which resveratrol imparts cancer chemopreventive effects has not been clearly defined. Earlier, we have shown that resveratrol treatment results in an induction of the cyclin kinase inhibitor WAF1/CIP1/p21 which, by inhibiting cyclin (E, D1, and D2) and cyclin-dependent kinases (cdk2, cdk4, and cdk6), results in a G0/G1-phase arrest followed by apoptosis of A431 human epidermoid carcinoma cells (Ahmad et al., Clin. Cancer Res. 7, 1466-1473, 2001). Retinoblastoma (pRb) and the E2F family of transcription factors are important proteins, which regulate the progression of the cell cycle at and near the G1-->S phase transition. Here we provide evidence for the involvement of the pRb-E2F/DP pathway as an important contributor of resveratrol-mediated cell cycle arrest and apoptosis. Immunoblot analysis demonstrated that resveratrol treatment of A431 cells results in a dose- as well as time-dependent decrease in the hyperphosphorylated form of pRb with a relative increase in hypophosphorylated pRb. This response was accompanied by downregulation of protein expression of all five E2F ( 1 - 5 ) family members of transcription factors studied and their heterodimeric partners DP1 and DP2. This suggests that resveratrol causes a downregulation of hyperphosphorylated pRb protein with a relative increase in hypophosphorylated pRb that, in turn, compromises with the availability of free E2F. We suggest that this series of events results in a stoppage of the cell cycle progression at the G1-->S phase transition thereby leading to a G0/G1 arrest and subsequent apoptotic cell death. To our knowledge, this is the first study showing the involvement of the pRb-E2F/DP pathway as a mechanism of the cancer-chemopreventive effects of resveratrol.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Proteins; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; G1 Phase; Humans; Resveratrol; Retinoblastoma Protein; Stilbenes; Transcription Factors; Tumor Cells, Cultured

WST-1 (mitochondrial dehydrogenase activities). Arrest of cell growth, due to inhibition of DNA synthesis, may explain the leveling of toxicity between day 2 and 3 for a 3-day continuous exposure to resveratrol. Irreversible damage to cell proliferation was noted in S-G cells exposed to 75-150 microM resveratrol for 2 days and then subsequently maintained for another 3 days in resveratrol-free medium. The cytotoxicity of resveratrol was neither potentiated nor ameliorated in the presence of an hepatic S9 microsomal fraction. The cytotoxicity of hydrogen peroxide to S-G cells was lessened by N-acetyl-L-cysteine and quercetin, but not by resveratrol. For nitric oxide, only N-acetyl-L-cysteine reduced toxicity. The ability of resveratrol to function as an antioxidant was, therefore, not noted under these test conditions.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antioxidants; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cell Count; Cell Division; Cell Line; Cell Survival; Coloring Agents; Cyclophosphamide; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Fibroblasts; Gingiva; Humans; Indicators and Reagents; Keratinocytes; Neutral Red; Oxazines; Resveratrol; Stilbenes; Tongue Neoplasms; Xanthenes

Topics: Anticarcinogenic Agents; Carcinoma, Squamous Cell; Cell Division; Humans; Mouth Neoplasms; Quercetin; Resveratrol; Stilbenes; Wine

Resveratrol and quercetin are polyphenols which have been detected in significant amounts in green vegetables, citrus fruits and red grape wines. Beneficial effects attributed to these compounds include anti-inflammatory, antiviral and antitumor properties. The effect of resveratrol and quercetin on growth of human oral cancer cells is unknown. Resveratrol and quercetin, in concentrations of 1 to 100 microM, were incubated in triplicates with human oral squamous carcinoma cells SCC-25 in DMEM-HAM's F-12 supplemented with fetal calf serum and antibiotics in an atmosphere of 5% CO2 in air at 37 degrees C for 72 h. Cell growth was determined by counting the number of viable cells with a hemocytometer. Cell proliferation was measured by means of incorporation of [3H]thymidine in nuclear DNA. Resveratrol at 10 and 100 microM induced significant dose-dependent inhibition in cell growth as well as in DNA synthesis. Quercetin exhibited a biphasic effect, stimulation at 1 and 10 microM, and minimal inhibition at 100 microM in cell growth and DNA synthesis. Combining 50 microM of resveratrol with 10, 25 and 50 microM of quercetin resulted in a gradual and significant increase in the inhibitory effect of quercetin on cell growth and DNA synthesis. We conclude that resveratrol or a combination of resveratrol and quercetin, in concentrations equivalent to that present in red wines, are effective inhibitors of oral squamous carcinoma cell (SCC-25) growth and proliferation, and warrant further investigation as cancer chemopreventive agents.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Division; Cisplatin; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Indomethacin; Quercetin; Resveratrol; Stilbenes; Tongue Neoplasms; Tumor Cells, Cultured

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Ear Neoplasms; Female; Male; Neoplasms, Experimental; Oxidoreductases; Rats; Stilbenes

Topics: Animals; Azocines; Carcinoma, Squamous Cell; Castration; Contraceptive Agents; Estradiol; Estriol; Estrogen Antagonists; Estrogens; Estrus; Female; Hexestrol; Injections, Subcutaneous; Leukocyte Count; Leukocytes; Mice; Naphthalenes; Ovary; Phenols; Pregnancy; Pyrrolidines; Stilbenes; Styrenes; Time Factors; Vagina; Vaginal Smears

Topics: Animals; Body Weight; Carcinogens; Carcinoma, Squamous Cell; Chromatography, Thin Layer; Diet; Ear Neoplasms; Ear, External; Female; Leukemia, Experimental; Male; Mammary Neoplasms, Experimental; Rats; Sex Factors; Spectrum Analysis; Stilbenes; Ultraviolet Rays

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cysts; Female; Keratoacanthoma; Male; Methylcholanthrene; Papilloma; Rats; Sebaceous Gland Neoplasms; Skin; Skin Neoplasms; Stilbenes

Topics: Animals; Body Weight; Carcinoma, Squamous Cell; Ear Neoplasms; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Rats; Sebaceous Gland Neoplasms; Stilbenes

Topics: Animals; Carcinoma, Squamous Cell; DNA, Neoplasm; Ear Neoplasms; Histocytochemistry; Neoplasms, Experimental; Rats; Stilbenes

Topics: Carcinoma; Carcinoma, Squamous Cell; Clomiphene; Endometrial Hyperplasia; Female; Hemorrhage; Humans; Metrorrhagia; Pathology; Stilbenes; Uterine Neoplasms

Topics: Antineoplastic Agents; Carcinogens; Carcinoma, Squamous Cell; Neoplasms; Neoplasms, Experimental; Rats; Research; Stilbenes; Toxicology