Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells

Sham S. Kakar, Mariusz Z. Ratajczak, Karen S. Powell, Mana Moghadamfalahi, Donald M. Miller, Surinder Kumar Batra, Sanjay K. Singh

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere107596
JournalPloS one
Volume9
Issue number9
DOIs
StatePublished - Sep 29 2014

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cisplatin
ovarian neoplasms
Neoplastic Stem Cells
Stem cells
metastasis
Ovarian Neoplasms
Cisplatin
stem cells
Tumors
Neoplasm Metastasis
Growth
neoplasms
Neoplasms
paclitaxel
Carboplatin
Cells
Paclitaxel
Bearings (structural)
Withania
Withania somnifera

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells. / Kakar, Sham S.; Ratajczak, Mariusz Z.; Powell, Karen S.; Moghadamfalahi, Mana; Miller, Donald M.; Batra, Surinder Kumar; Singh, Sanjay K.

In: PloS one, Vol. 9, No. 9, e107596, 29.09.2014.

Research output: Contribution to journalArticle

Kakar, Sham S. ; Ratajczak, Mariusz Z. ; Powell, Karen S. ; Moghadamfalahi, Mana ; Miller, Donald M. ; Batra, Surinder Kumar ; Singh, Sanjay K. / Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells. In: PloS one. 2014 ; Vol. 9, No. 9.
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