Abstract
Circadian time-dependent treatment with chemotherapeutic drugs (chronotherapy) optimizes the therapeutic index by maximizing treatment efficacy and minimizing toxicity. The circadian time-dependent chemopreventive and anti-lipid peroxidative efficacy of withaferin-A in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated in the present study. We induced oral squamous cell carcinoma in the buccal pouches of golden Syrian hamsters during the day (4:00, 8:00, 12:00,16:00, 20:00 and 24:00) by application of DMBA three times per week for 14 weeks. The circadian time-dependent tumor incidence, volume and burden were observed in hamsters treated with either DMBA alone or DMBA + withaferin-A. The circadian pattern of lipid peroxidation by-products, as measured by the formation of thiobarbituric acid reactive substances (TBARS) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], was also analyzed in the buccal mucosa of DMBA-treated hamsters. We found the highest incidence of tumor formation at 24.00h in hamsters treated with DMBA alone as compared to other experimental groups. Circadian dysregulation of lipid peroxidation and antioxidant status was observed in DMBA-treated animals as compared to control animals. Oral (po) administration of withaferin-A (20mg/kg) completely prevented the formation of tumors between 8.00h and 12.00h and synchronized the status of lipid peroxidation and antioxidants in the buccal mucosa of hamsters treated with DMBA alone. Also, oral administration of withaferin-A to DMBA-treated animals significantly reduced the formation of tumors and synchronized the status of lipid peroxidation and antioxidants in the rest of the time intervals. Our study thus suggests that withaferin-A has significant chemopreventive and anti-lipid peroxidative potential in DMBA-induced oral carcinogenesis, probably by interfering with DMBA-induced abnormal cell proliferation in the buccal mucosa.
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