Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells
Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells
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DOI：
10.3390/ijms21072327
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Min, Sang-Hyun
中科院分区：
文献类型：
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作者：
Lee, Heejin;Kim, Jun Woo;Min, Sang-Hyun
据报道，上皮性卵巢癌（EOC）的耐药归因于癌症干细胞（CSC）的存在，因为在大多数癌症中，化疗后CSC仍然存在。为了克服这一限制，需要新的治疗策略，通过靶向癌症干细胞（CSCs）来预防癌症复发和化疗耐药癌症。我们筛选了一个fda批准的化合物库，发现了四种电压门控钙通道阻滞剂（曼尼地平、拉西地平、苯尼地平和洛美嗪）靶向卵巢csc。四种钙通道阻滞剂（CCBs）可降低卵巢csc的球形形成、活力和增殖，并诱导凋亡。CCBs破坏卵巢CSCs的干性，抑制AKT和ERK信号通路。在钙通道亚基基因中，3个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。这三个基因的表达与患者组生存率呈负相关。在与顺铂联合治疗时，显示出协同作用，抑制卵巢csc的活力和增殖。此外，联合使用曼地平和紫杉醇在卵巢CSCs异种移植小鼠模型中显示出增强的效果。我们的研究结果表明，四种CCBs可能是预防卵巢癌复发的潜在治疗药物。
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.