title: Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, United States of America; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Sham S
authors.initials: SS
authors.lastname: Kakar
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Medicine, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
authors.affiliation: Research Resources Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Powell
authors.affiliation: Department of Pathology, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Mana
authors.initials: M
authors.lastname: Moghadamfalahi
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America; Department of Medicine, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky, United States of America; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D054358:Withanolides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014408:Biomarkers, Tumor; D054358:Withanolides; C009684:withaferin A; D002945:Cisplatin