Abstract
Ovarian Cancer is the fifth leading cause of death among women from cancer. Cancer stem cells are a small population of cells present in cancer and the cause of chemoresistance and recurrence of cancer. We tested a new compound “Verrucarin J (VJ)”, a metabolite of the Myrothecium fungus family, and showed that VJ significantly inhibits cell proliferation of both cisplatin-sensitive (A2780 and OVCAR5) and cisplatin-resistant (A2780/CP70) cell lines in a dose- and time-dependent manner with IC50 value of approximately 10 nM after 48 h of treatment. VJ was found to induce apoptosis, DNA damage, and generation of reactive oxygen species (ROS). Treatment of A2780 cells with VJ resulted in a significant suppression of expression of CSCs markers including ALDH1, LGR5, NANOG and OCT4 in a dose-dependent manner, elimination of ALDH1+ CSC population and inhibition of expression of Notch1 and Wnt1 signaling pathways. Our study also showed that VJ inhibited the tumorigenic potential (spheroid formation on ultralow attachment plates) of isolated ALDH1+ CSCs in vitro and tumor growth and metastasis in vivo. VJ resulted downregulation of expression of securin an “oncogene” involved in tumor growth and progression, indicating that securin may serve as a downstream signaling gene to mediate antitumor effects of VJ.
Highlights
Ovarian cancer is the fifth leading cause of deaths due to cancer among women in the United States [1]
Various populations of cancer stem cells (CSCs) have been reported in ovarian tumor cell lines, ovarian tumors, and ascites collected from patients with ovarian cancer [10,11,12,13,14,15,16,17,18]
In our previous studies in vivo, we showed a significant increase in CSCs: CD24, CD34, CD44, CD117, ALDH1 and OCT4, in tumors collected from animals bearing orthotopic ovarian cancer followed by treatment with cisplatin [20, 21]
Summary
Ovarian cancer is the fifth leading cause of deaths due to cancer among women in the United States [1]. The most common treatment for ovarian cancer is cytoreductive surgery followed by chemotherapy consisting of a platinum/taxane combination [2, 3]. This chemotherapeutic treatment shows a high response rate, within 18 to 24 months, most of the patients (70 to 80%) develop resistance to cisplatin resulting in tumor relapse and succumb to their disease within 5 years of their diagnosis [3, 4]. The most common CSCs identified include CD24, CD34, CD44, CD117, ALDH1, EpCAM, SSEA4, NANOG, MYD88, and SOX2 positive cells [13].
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