gingerol and Mouth-Neoplasms

The present study examines the chemopreventive role of [6]-gingerol, an active component of ginger, on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis models. The HBP has been developed with an addition of 0.5% of DMBA to the HBP area three times per week, up to the end of the 16th experimental week. At the end of the experiment, we noticed 100% tumor incidence and precancerous lesions, such as dysplasia, hyperplasia, keratosis, and well-differentiated squamous cell carcinoma, in DMBA-induced HBP. Furthermore, we observed that [6]-gingerol inhibited the increased thiobarbituric acid-reactive substances and decreased antioxidant levels in DMBA-induced hamsters. Moreover, [6]-gingerol inhibits DMBA-exposed over expression of inflammatory markers (inducible nitric oxide synthase, interleukin [IL]-1β, IL-6, cyclooxygenase-2, and tumor necrosis factor-α) and cell proliferation markers (cyclin D1, proliferating cell nuclear antigen); induces proapoptotic markers in HBP. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a major antioxidant transcription factor, which regulates the antioxidant gene-dependent scavenge of tumor proliferation and apoptosis. Overexpression of Nrf2 signaling plays a pivotal role and can be a novel target in preventing carcinogenesis. In this study, [6]-gingerol restores the DMBA-induced depletion of Nrf2 signaling and thereby prevents buccal pouch carcinogenesis in hamsters. These results point out that [6]-gingerol impedes the responses of inflammatory and cell proliferation-associated progression of cancer through the action of Nrf2 signaling.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogenesis; Catechols; Cell Proliferation; Fatty Alcohols; Inflammation; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Neoplasm Proteins; NF-E2-Related Factor 2; Signal Transduction

6-Gingerol, a potent nutraceutical, has been shown to have antitumor activity in different tumors, although its mechanism of action is not well understood. In this study, we evaluated antitumor activities of 6-gingerol on human oral (SCC4, KB) and cervical cancer (HeLa) cell lines with or without wortmannin, rapamycin, and cisplatin. Tumor cell proliferation was observed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt assay, cell cycle analysis by propidium iodide labeling and flow cytometry, apoptosis by Annexin-V binding assay, and caspase activity by chemiluminescence assay. 6-Gingerol showed dose-dependent cytotoxicity in all three cell lines. Combinations of 6-gingerol with wortmannin and cisplatin showed additive effects, while with rapamycin, it showed 50% cytotoxicity that was equivalent to IC50 of 6-gingerol alone. Treatment with 6-gingerol resulted in G2-phase arrest in KB and HeLa cells and S-phase arrest in SCC4 cells. 6-Gingerol, wortmannin, and rapamycin treatment showed almost two-fold higher expression of caspase 3 in all cell lines. The results imply that 6-gingerol either alone or in combination with PI-3 K inhibitor and cisplatin may provide better therapeutic effects in oral and cervical carcinoma. Thus, 6-gingerol appears to be a safe and potent chemotherapeutic/chemopreventive compound acting through cell cycle arrest and induction of apoptosis in human oral and cervical tumor cells.

Topics: Androstadienes; Apoptosis; Caspase 3; Catechols; Cell Cycle Checkpoints; Cell Division; Cell Line, Tumor; Cell Proliferation; Cisplatin; Fatty Alcohols; Female; HeLa Cells; Humans; Mouth Neoplasms; Sirolimus; Uterine Cervical Neoplasms; Wortmannin

The effect of [6]-shogaol (1) on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)) and viability has not been explored previously in oral epithelial cells. The present study has examined whether 1 alters [Ca(2+)](i) and viability in OC2 human oral cancer cells. Compound 1 at concentrations > or = 5 microM increased [Ca(2+)](i) in a concentration-dependent manner with a 50% effective concentration (EC(50)) value of 65 microM. The Ca(2+) signal was reduced substantially by removing extracellular Ca(2+). In a Ca(2+)-free medium, the 1-induced [Ca(2+)](i) elevation was mostly attenuated by depleting stored Ca(2+) with thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor). The [Ca(2+)](i) signal was inhibited by La(3+) but not by L-type Ca(2+) channel blockers. The elevation of [Ca(2+)](i) caused by 1 in a Ca(2+)-containing medium was not affected by modulation of protein kinase C activity, but was inhibited by 82% with the phospholipase A2 inhibitor aristolochic acid I (20 microM). U73122, a selective inhibitor of phospholipase C, abolished 1-induced [Ca(2+)](i) release. At concentrations of 5-100 microM, 1 killed cells in a concentration-dependent manner. These findings suggest that [6]-shogaol induces a significant rise in [Ca(2+)](i) in oral cancer OC2 cells by causing stored Ca(2+) release from the thapsigargin-sensitive endoplasmic reticulum pool in an inositol 1,4,5-trisphosphate-dependent manner and by inducing Ca(2+) influx via a phospholipase A2- and La(3+)-sensitive pathway.

Topics: Calcium; Calcium Channels, L-Type; Catechols; Cell Line, Tumor; Cytosol; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Estrenes; Humans; Inositol 1,4,5-Trisphosphate; Molecular Structure; Mouth Neoplasms; Phospholipase A2 Inhibitors; Protein Kinase C; Pyrrolidinones; Thapsigargin