New Drug Development Center, DGMIF, 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea.
School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea.
Int J Mol Sci. 2020 Mar 27;21(7):2327. doi: 10.3390/ijms21072327.
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.
上皮性卵巢癌（EOC）的耐药性据报道归因于癌症干细胞（CSC）的存在，因为在大多数癌症中，化疗后CSC 仍然存在。为了克服这一局限性，需要新的治疗策略来通过靶向癌症干细胞（CSC）来预防癌症复发和化疗耐药性癌症。我们筛选了 FDA 批准的化合物库，发现了四种靶向卵巢 CSC 的电压门控钙通道阻滞剂（马尼地平、拉西地平、贝尼地平、和洛美利嗪）。四种钙通道阻滞剂（CCBs）可减少球体形成、活力和增殖，并诱导卵巢 CSCs 凋亡。CCBs 破坏了干细胞特性，并抑制了卵巢 CSCs 中的 AKT 和 ERK 信号通路。在钙通道亚基基因中，三种 L 型和 T 型钙通道基因在卵巢 CSCs 中过表达，钙通道基因的下调降低了卵巢 CSCs 的干细胞样特性。这些三个基因的表达与患者群体的存活率呈负相关。与顺铂联合治疗时，联合治疗显示出抑制卵巢 CSCs 活力和增殖的协同作用。此外，马尼地平和紫杉醇联合使用在卵巢 CSCs 异种移植小鼠模型中显示出增强作用。我们的研究结果表明，四种 CCB 可能是预防卵巢癌复发的潜在治疗药物。
