Abstract
Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.
Highlights
Ovarian cancer is known as the most lethal gynecologic malignancy; the overall 5-year survival rate for epithelial ovarian cancer (EOC) remains almost 30% [1]
We found that four calcium channel blockers showed anticancer effects against ovarian cancer stem cells (CSC) by reducing stemness and inducing apoptosis in CSCs
We confirmed whether A2780-SP cells exhibited CSC characteristics compared with their parental ovarian cancer cell line A2780 cells
Summary
Ovarian cancer is known as the most lethal gynecologic malignancy; the overall 5-year survival rate for epithelial ovarian cancer (EOC) remains almost 30% [1]. Despite general treatment success with a combination therapy of surgical resection of tumor mass and chemotherapy, an unacceptably high number of patients (70%) develop terminal, recurrent, and chemotherapy-resistant disease [3]. To overcome this treatment limitation, novel treatments are needed to prevent the development of recurrent and chemotherapy-resistant disease by targeting cancer stem cells (CSCs). CSCs are defined as subpopulations of cells within a tumor that possess the capacity for self-renewal and generate heterogeneous lineages of cancer cells in the tumor [4,5]. CSCs generally constitute only a small minority of cancer cell populations; high-throughput screening of drugs that selectively target CSCs depends on in vitro propagation of stable and highly enriched populations of CSCs
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