stilbenes and Mouth-Neoplasms

Nutraceuticals with anti-neoplastic potential are suitable candidates for extending the range of therapeutic options for several types of cancers. One of these malignancies is oral cancer of the squamous cell carcinoma type, for which current treatment approaches have not succeeded in improving long-term clinical outcome. We recently reviewed the beneficial effects of curcumin for the treatment of oral cancer. In the current review, we focused on the beneficial effects of other two nutraceuticals, green tea extracts [especially (-)-epigallocatechin-3-gallate (EGCG)] and resveratrol, in the treatment of oral cancer. In vivo and in vitro studies as well as clinical trials were reviewed, focusing on the beneficial effect of each of these plant-derived dietary agents, either alone or in combination with various pharmacological agents. We also presented the anti-cancer effects against cancer cells and against components of the tumor microenvironment. It emerged that the poor bioavailability of these nutraceuticals poses an obstacle to their exerting adequate anti-cancer potential. Ground-breaking studies employing new nanotechnology-based therapeutic approaches were presented.

Topics: Animals; Catechin; Dietary Supplements; Humans; Mice; Mouth Neoplasms; Plant Extracts; Resveratrol; Stilbenes; Tea

Oral cancer represents a health burden worldwide with approximate 275,000 new cases diagnosed annually. Its poor prognosis is due to local tumor invasion and frequent lymph node metastasis. Better understanding and development of novel treatments and chemo-preventive approaches for the preventive and therapeutic intervention of this type of cancer are necessary. Recent development of dietary polyphenols as cancer preventives and therapeutic agents is of great interest due to their antioxidant and anti-carcinogenic activities. Polyphenols may inhibit carcinogenesis in the stage of initiation, promotion, or progression. In particular, dietary polyphenols decrease incidence of carcinomas and exert protection against oral cancer by induction of cell death and inhibition of tumor growth, invasion, and metastasis. In this review, we discuss current progress of dietary polyphenols against oral cancers in vitro, in vivo, and at population levels.

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Biological Availability; Chemoprevention; Diet; Ellagic Acid; Flavonoids; Humans; Mouth Neoplasms; Phytotherapy; Polyphenols; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Tea

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

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

The aim of this study was to develop a new drug substance with low toxicity and effective inhibitory activity against cisplatin-resistant oral cancer. The naturally produced pterostilbene was selected as the lead compound for design and synthesis of a series of bis(hydroxymethyl)propionate-based prodrugs. All derivatives were screened for antiproliferative effects against the cisplatin-resistant oral squamous (CAR) cell line and the results indicated that several compounds demonstrated superior inhibitory activity compared with pterostilbene and resveratrol. Among them, the most promising compound, 12, was evaluated for in vivo antitumor activity in a CAR xenograft nude mouse model. Obvious antitumor activity was observed at the lowest oral dose (25 mg/kg/day). Increasing the dose of 12 to 100 mg/kg/day reduced the tumor size to 22% of the control group. Based on these findings as well as the extremely low toxicity seen in the in vivo studies, we believe that compound 12 could serve as a new lead for further development.

Topics: Antineoplastic Agents; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Mouth Neoplasms; Propionates; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

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

Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.

Topics: Amino Acid Chloromethyl Ketones; AMP-Activated Protein Kinases; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Autophagy-Related Protein 12; Autophagy-Related Protein 5; Beclin-1; Caspase 3; Caspase 9; Cell Line, Tumor; Cisplatin; DNA Fragmentation; Drug Resistance, Neoplasm; Humans; Microtubule-Associated Proteins; Mouth Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases

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

Oral submucous fibrosis (OSF) is a precancerous condition of the oral mucosa without specific therapeutic drugs. We previously demonstrated that the zinc finger E-box binding homeobox 1 (ZEB1) plays a pathogenic role in the induction of the myofibroblast activity of buccal mucosal fibroblasts (BMFs) and contributes to the pathogenesis of OSF. Resveratrol is a natural polyphenolic flavonoid with anti-fibrosis activity in various tissues and has the capability to inhibit ZEB1 in oral cancer cells. We examined the effect of resveratrol on the myofibroblast activity of human primary fibrotic BMFs (fBMFs) derived from OSF tissues. With the collagen contraction assay, resveratrol displayed anti-myofibroblast activity in three fBMF lines. Resveratrol also inhibited the expression of fibrogenic genes at the mRNA and protein levels in a dose- and time-dependent manner. The downregulation of ZEB1 in fBMFs by resveratrol was mediated by epigenetic mechanisms, such as the upregulated expression of miR-200c and the enhancer of zeste homolog 2 (EZH2), as well as the trimethylated lysine 27 of histone H3 (H3K27me3). Resveratrol also increased the binding of H3K27me3 to the ZEB1 promoter. The knockdown of EZH2 in fBMFs caused the upregulation of ZEB1 and suppressed the inhibitory effect of resveratrol. Furthermore, the reversed expression pattern between EZH2 and ZEB1 was observed in 6/8 OSF tissues with twofold upregulation of ZEB1 expression compared with the adjacent normal mucosa. In conclusion, our data suggest that resveratrol epigenetically inhibits ZEB1 expression to suppress the myofibroblast activity of fBMFs and may serve as a dietary supplement for OSF patients.

Topics: Enhancer of Zeste Homolog 2 Protein; Epigenomics; Fibroblasts; Humans; Mouth Mucosa; Mouth Neoplasms; Myofibroblasts; Oral Submucous Fibrosis; Precancerous Conditions; Resveratrol; Stilbenes; Zinc Finger E-box-Binding Homeobox 1

Resveratrol is a natural compound that affects cellular calcium (Ca(2+)) homeostasis and viability in different cells. This study examined the effect of resveratrol on cytosolic free Ca(2+) concentrations ([Ca(2+)]i) and viability in OC2 human oral cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)]i, and water-soluble tetrazolium-1 was used to measure viability. Resveratrol evoked concentration-dependent increase in [Ca(2+)]i. The response was reduced by removing extracellular Ca(2+). Resveratrol also caused manganese-induced fura-2 fluorescence quench. Resveratrol-evoked Ca(2+) entry was inhibited by nifedipine and the protein kinase C (PKC) inhibitor GF109203X but was not altered by econazole, SKF96365, and the PKC activator phorbol 12-myristate 13 acetate. In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished resveratrol-evoked [Ca(2+)]i rise. Conversely, treatment with resveratrol inhibited BHQ-evoked [Ca(2+)]i rise. Inhibition of phospholipase C (PLC) with U73122 abolished resveratrol-evoked [Ca(2+)]i rise. At 20-100 μM, resveratrol decreased cell viability, which was not affected by chelating cytosolic Ca(2+)with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester. Annexin V-fluorescein isothiocyanate staining data suggest that resveratrol at 20-40 μM induced apoptosis in a concentration-dependent manner. Collectively, in OC2 cells, resveratrol induced [Ca(2+)]i rise by evoking PLC-dependent Ca(2+) release from the endoplasmic reticulum and by causing Ca(2+) entry via nifedipine-sensitive, PKC-regulated mechanisms. Resveratrol also caused Ca(2+)-independent apoptosis.

Topics: Apoptosis; Calcium; Cell Line, Tumor; Cell Survival; Cytosol; Humans; Mouth Neoplasms; Protein Kinase C; Resveratrol; Stilbenes; Type C Phospholipases

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

Extensive research supports the administration of herbal medicines or natural foods during cancer therapy. Pterostilbene, a naturally occurring phytoalexin, has various pharmacological activities, including antioxidant activity, cancer prevention activity, and cytotoxicity to many cancers. However, the effect of pterostilbene on the autophagy of tumor cells has not been clarified.. In this study, the unique effects of pterostilbene on the autophagy of human oral cancer cells were investigated.. The results of this study showed that pterostilbene effectively inhibited the growth of human oral cancer cells by inducing cell cycle arrest and apoptosis. In addition, the formation of acidic vesicular organelles and LC3-II production also demonstrated that pterostilbene induced autophagy. Administering 3-methylamphetamine (3-MA) and bafilomycin A1 (BafA1) exerted differing effects on the pterostilbene-induced death of human oral cancer cells. Pterostilbene-induced autophagy was triggered by activation of JNK1/2 and inhibition of Akt, ERK1/2, and p38.. In conclusion, this study demonstrated that pterostilbene caused autophagy and apoptosis in human oral cancer cells, suggesting that pterostilbene could serve as a new and promising agent for treating human oral cancer.

Topics: Amphetamines; Apoptosis; Autophagy; Cell Cycle Checkpoints; Enzyme Inhibitors; Humans; Macrolides; MAP Kinase Signaling System; Microtubule-Associated Proteins; Mitogen-Activated Protein Kinases; Mouth Neoplasms; Organelles; Proto-Oncogene Proteins c-akt; Stilbenes

Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine.

Topics: Administration, Oral; Algorithms; Antineoplastic Agents; Berberine; Bortezomib; Colchicine; Databases, Pharmaceutical; Databases, Protein; Diterpenes; Humans; Hydroxamic Acids; Limonins; Lovastatin; Models, Statistical; Mouth Neoplasms; Predictive Value of Tests; Resveratrol; Rotenone; Stilbenes; Support Vector Machine; Vorinostat

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

Pterostilbene is an effective chemopreventive agent against multiple types of cancer cells. A novel pterostilbene derivative, ANK-199, was designed and synthesized by our group. Its antitumor activity and mechanism in cisplatin-resistant CAR human oral cancer cells were investigated in this study. Our results show that ANK-199 has an extremely low toxicity in normal oral cell lines. The formation of autophagic vacuoles and acidic vesicular organelles (AVOs) was observed in the ANK-199-treated CAR cells by monodansylcadaverine (MDC) and acridine orange (AO) staining, suggesting that ANK-199 is able to induce autophagic cell death in CAR cells. Neither DNA fragmentation nor DNA condensation was observed, which means that ANK-199-induced cell death is not triggered by apoptosis. In accordance with morphological observation, 3-MA, a specific inhibitor of PI3K kinase class III, can inhibit the autophagic vesicle formation induced by ANK-199. In addition, ANK-199 is also able to enhance the protein levels of autophagic proteins, Atg complex, beclin 1, PI3K class III and LC3-II, and mRNA expression of autophagic genes Atg7, Atg12, beclin 1 and LC3-II in the ANK-199-treated CAR cells. A molecular signaling pathway induced by ANK-199 was therefore summarized. Results presented in this study show that ANK-199 may become a novel therapeutic reagent for the treatment of oral cancer in the near future (patent pending).

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Blotting, Western; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Resistance, Neoplasm; Humans; Membrane Proteins; Mouth Neoplasms; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Polymerase Chain Reaction; Stilbenes

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

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

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

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