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联合波齐替尼和马尼地平治疗可抑制卵巢癌干细胞的增殖和干性。

Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness.

机构信息

New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea.

BK21 Plus KNU Creative BioResearch Group, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 41566, Korea.

出版信息

Int J Mol Sci. 2020 Oct 6;21(19):7379. doi: 10.3390/ijms21197379.

DOI:10.3390/ijms21197379
PMID:33036254
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7583017/
Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in women worldwide, with an overall 5 year survival rate below 30%. The low survival rate is associated with the persistence of cancer stem cells (CSCs) after chemotherapy. Therefore, CSC-targeting strategies are required for successful EOC treatment. Pan-human epidermal growth factor receptor 4 (HER4) and L-type calcium channels are highly expressed in ovarian CSCs, and treatment with the pan-HER inhibitor poziotinib or calcium channel blockers (CCBs) selectively inhibits the growth of ovarian CSCs via distinct molecular mechanisms. In this study, we tested the hypothesis that combination treatment with poziotinib and CCBs can synergistically inhibit the growth of ovarian CSCs. Combined treatment with poziotinib and manidipine (an L-type CCB) synergistically suppressed ovarian CSC sphere formation and viability compared with either drug alone. Moreover, combination treatment synergistically reduced the expression of stemness markers, including CD133, KLF4, and NANOG, and stemness-related signaling molecules, such as phospho-STAT5, phospho-AKT, phospho-ERK, and Wnt/β-catenin. Moreover, poziotinib with manidipine dramatically induced apoptosis in ovarian CSCs. Our results suggest that the combinatorial use of poziotinib with a CCB can effectively inhibit ovarian CSC survival and function.

摘要

上皮性卵巢癌 (EOC) 是全球女性中最致命的妇科恶性肿瘤，总体 5 年生存率低于 30%。低生存率与化疗后癌症干细胞 (CSC) 的持续存在有关。因此，需要针对 CSC 的靶向策略来成功治疗 EOC。全人表皮生长因子受体 4 (HER4) 和 L 型钙通道在上皮性卵巢 CSC 中高度表达，用 pan-HER 抑制剂波齐替尼或钙通道阻滞剂 (CCB) 治疗通过不同的分子机制选择性抑制卵巢 CSC 的生长。在这项研究中，我们检验了这样一个假设，即波齐替尼和 CCB 的联合治疗可以协同抑制卵巢 CSC 的生长。与单独使用任一药物相比，波齐替尼和马尼地平（一种 L 型 CCB）联合治疗可协同抑制卵巢 CSC 球体形成和活力。此外，联合治疗还协同降低了干性标志物，包括 CD133、KLF4 和 NANOG，以及干性相关信号分子，如磷酸化 STAT5、磷酸化 AKT、磷酸化 ERK 和 Wnt/β-catenin 的表达。此外，波齐替尼与马尼地平联合可显著诱导卵巢 CSC 凋亡。我们的研究结果表明，波齐替尼与 CCB 的联合使用可有效抑制卵巢 CSC 的存活和功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/8c554c2ecba7/ijms-21-07379-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/577c70109c40/ijms-21-07379-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/08513cc02e90/ijms-21-07379-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/77e9e62545ce/ijms-21-07379-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/8c554c2ecba7/ijms-21-07379-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/577c70109c40/ijms-21-07379-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/08513cc02e90/ijms-21-07379-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bce5/7583017/3e09f27d7acb/ijms-21-07379-g003.jpg
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