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.
Highlights
Epithelial ovarian cancer (EOC) remains the leading cause of death in women among gynecologic cancers and is the 5th highest cause of cancer-related deaths in women in the United States [1,2]
In our previous studies [10], we showed for a first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with CIS had a time- and dose-dependent synergistic effect on inhibition of cell proliferation and induction of cell death, reducing required dosage of cisplatin
We show for the first time that WFA alone or in combination with CIS if employed to treat mice bearing human orthotopic ovarian tumors suppresses tumor growth but targets cells expressing cancer stem cells (CSCs) markers as well as inhibits Notch1 and its downstream signaling genes (Hes1 and Hey1) that have been reported to play a crucial role in self-renewal and maintenance of CSCs (33)
Summary
Epithelial ovarian cancer (EOC) remains the leading cause of death in women among gynecologic cancers and is the 5th highest cause of cancer-related deaths in women in the United States [1,2]. The majority of ovarian cancers are diagnosed at advanced stage due to the mainly non-specific symptoms. The treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, employing mainly platinum/taxane combination [3]. This regimen is initially effective in a high percentage of cases (70 to 80%), 70% of women develop recurrent cancer within few months of initial treatment as a result of platinum-resistance [4,5]. Need for new treatment options that target cancer cells and in particular putative cancer stem cells is mandatory either at first-line setting or even more at the first- and second-line management of recurrent ovarian cancer
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