withaferin-a and Skin-Neoplasms

Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc.

Topics: Acetyl-CoA Carboxylase; Animals; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mice; Skin Neoplasms; Transcription Factor AP-1; Up-Regulation; Withanolides; Xenograft Model Antitumor Assays

Withaferin A (WA), isolated from Indian medicinal plant Withania somnifera has weak antitumor and radiosensitizing property. The present investigation was planned to evaluate the tumor sensitizing effect of WA with or without local hyperthermia on the response of B16F1 melanoma to fractionated and acute radiotherapy. C57BL mice bearing tumors of 100 ± 10 mm³ were treated with fractionated radiotherapy (RT, 2 Gy x 5 days/week, 4 weeks), withaferin A (15 mg/kg, i.p., 5 days/ week, 3 weeks), local hyperthermia (HT, 43°C once a week, 3 weeks) and their combinations, or acute RT (40 Gy), WA (40 mg/kg), HT (43°C, 30 min) and their combinations. Treatment response was studied by tumor regression, growth delay and animal survival. Acute RT+HT produced 50% partial response which increased to 62.5% with combination of WA. In fractionated regimen, trimodality combination resulted in 100% PR. Acute RT+HT and WA+RT produced similar increase in growth delay (GD) compared to RT alone which further increased in trimodality treatment. Fractionated WA+RT+HT for 3 weeks produced a higher GD and survival than all other treatments. In conclusion, WA is a better radiosensitizer than HT in fractionated regimen and the response of radioresistant tumors like melanoma can be significantly enhanced by combining nontoxic doses of WA with fractionated RT, with or without HT, allowing decrease in radiation dose.

Topics: Animals; Antineoplastic Agents; Combined Modality Therapy; Dose Fractionation, Radiation; Hyperthermia, Induced; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Radiotherapy, Adjuvant; Skin Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; Withanolides