Currently, the treatment for
ovarian cancer entails
cytoreductive surgery followed by
chemotherapy, mainly,
carboplatin combined with
paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment,
tumor relapse occurs because of
platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that
withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with
cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian
tumors generated by injecting human
ovarian epithelial cancer cell line (A2780) with WFA and
cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in
tumor growth and complete inhibition of
metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the
tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in
tumors exposed to CIS may explain recurrence of
cancer in patients treated with
carboplatin and
paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious
therapy for
ovarian cancer.