title: Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis.
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 24.00 h 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 (20 mg/kg) completely prevented the formation of tumors between 8.00 h and 12.00 h 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.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar-608 002, Tamil Nadu, India. rasmanshisak@gmail.com
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Manoharan
authors.forename: Kuppusamy
authors.initials: K
authors.lastname: Panjamurthy
authors.forename: Subramanian
authors.initials: S
authors.lastname: Balakrishnan
authors.forename: Kalaiarasan
authors.initials: K
authors.lastname: Vasudevan
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Vellaichamy
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000302:isolation & purification / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D006224:Cricetinae; D004875:Ergosterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000627:therapeutic use; D008297:Male; D008647:Mesocricetus; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000008:administration & dosage / Q000302:isolation & purification / Q000627:therapeutic use; D018517:Plant Roots; D054358:Withanolides
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D010936:Plant Extracts; D054358:Withanolides; D015127:9,10-Dimethyl-1,2-benzanthracene; C009684:withaferin A; D004875:Ergosterol