stilbenes and Head-and-Neck-Neoplasms

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

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

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

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

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

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

Recent reports have demonstrated that head and neck cancer-derived tumor-initiating cells (HNC-TICs) presented high tumorigenic, chemoradioresistant, metastatic properties, and were coupled with gain of epithelial-mesenchymal transition (EMT) characteristics. The aim of this study was to investigate the chemotherapeutic effect and regulatory mechanisms of resveratrol on HNC-TICs.. We first observed that the treatment of resveratrol significantly downregulated the ALDH1 activity and CD44 positivity of head and neck cancer (HNC) cells in a dose-dependent manner (p < 0.05). Moreover, resveratrol treatment reduced self-renewal property and stemness genes signatures (Oct4, Nanog, and Nestin) expression in sphere-forming HNC-TICs. Additionally, the repressive effect of resveratrol on in vitro malignant properties including invasiveness/anchorage-independent growth was mediated by regulating productions of EMT markers Slug, ZEB1, N-cadherin, E-cadherin, and Vimentin. Importantly, an in vivo nude mice model showed that resveratrol treatment to xenograft tumors by oral gavage reduced tumor growth, stemness, and EMT markers in vivo. Lastly, synergistic effect of resveratrol and conventional chemotreatment attenuated tumor-initiating cells property in HNC-TICs.. Our results demonstrated that resveratrol would be a valuable therapeutics clinically in combination with conventional chemotherapy treatment modalities for malignant HNCs by elimination of tumor-initiating stem-like and EMT properties.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Survival; Epithelial Cells; Epithelial-Mesenchymal Transition; Gingiva; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Isoenzymes; Mice; Mice, Nude; Neoplastic Stem Cells; Resveratrol; Retinal Dehydrogenase; Stilbenes; Xenograft Model Antitumor Assays

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

Cyclooxygenase-2 (COX-2) content is increased in many types of tumor cells. We have investigated the mechanism by which resveratrol, a stilbene that is pro-apoptotic in many tumor cell lines, causes apoptosis in human head and neck squamous cell carcinoma UMSCC-22B cells by a mechanism involving cellular COX-2. UMSCC-22B cells treated with resveratrol for 24 h, with or without selected inhibitors, were examined: (1) for the presence of nuclear activated ERK1/2, p53 and COX-2, (2) for evidence of apoptosis, and (3) by chromatin immunoprecipitation to demonstrate p53 binding to the p21 promoter. Stilbene-induced apoptosis was concentration-dependent, and associated with ERK1/2 activation, serine-15 p53 phosphorylation and nuclear accumulation of these proteins. These effects were blocked by inhibition of either ERK1/2 or p53 activation. Resveratrol also caused p53 binding to the p21 promoter and increased abundance of COX-2 protein in UMSCC-22B cell nuclei. Resveratrol-induced nuclear COX-2 accumulation was dependent upon ERK1/2 activation, but not p53 activation. Activation of p53 and p53-dependent apoptosis were blocked by the COX-2 inhibitor, NS398, and by transfection of cells with COX-2-siRNA. In UMSCC-22B cells, resveratrol-induced apoptosis and induction of nuclear COX-2 accumulation share dependence on the ERK1/2 signal transduction pathway. Resveratrol-inducible nuclear accumulation of COX-2 is essential for p53 activation and p53-dependent apoptosis in these cancer cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Nucleus; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 2; Drug Screening Assays, Antitumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Head and Neck Neoplasms; Humans; MAP Kinase Signaling System; Models, Biological; Neoplasms, Squamous Cell; Nitrobenzenes; p38 Mitogen-Activated Protein Kinases; Phosphoserine; Promoter Regions, Genetic; Protein Binding; Protein Kinase Inhibitors; Resveratrol; Stilbenes; Subcellular Fractions; Sulfonamides; Tumor Suppressor Protein p53

Topics: Anaphylaxis; Aniline Compounds; Head; Head and Neck Neoplasms; Hemangioma; Humans; Hypersensitivity; Neck; Neoplasms; Stilbenes