Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells.

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.

• Authors: Heejin Lee, Jun Woo Kim, Dae Kyung Kim, Dong Kyu Choi, Seul Lee, Ji Hoon Yu, Oh-Bin Kwon, Jungsul Lee, Dong-Seok Lee, Jae Ho Kim, Sang-Hyun Min
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 7 (Mar 27 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32230901 (Publication Type: Journal Article)

Chemical References

• Antihypertensive Agents
• Calcium Channel Blockers
• Calcium Channels
• Dihydropyridines
• Nitrobenzenes
• Piperazines
• lacidipine
• benidipine
• manidipine
• lomerizine
• Paclitaxel
• Cisplatin

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Apoptosis (drug effects)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (drug effects, metabolism)
• Carcinoma, Ovarian Epithelial
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Dihydropyridines (pharmacology)
• Drug Repositioning
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Neoplastic Stem Cells (drug effects, metabolism)
• Nitrobenzenes
• Ovarian Neoplasms
• Paclitaxel (pharmacology)
• Piperazines (pharmacology)
• Signal Transduction (drug effects, genetics)
• Tumor Microenvironment (drug effects)