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

International Journal of Molecular Sciences

Dong-Seok Lee¹  JunWoo Kim²  Sang-Hyun Min²  Heejin Lee² 

[1] BK21 Plus KNU Creative BioResearch Group, School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 41566, Korea;New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbok-ro, Dong-gu, Daegu 41061, Korea;

关键词: drug synergism;    poziotinib;    manidipine;    cancer stem cells;    stemness;    Wnt/β-catenin;   

DOI  :  10.3390/ijms21197379

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown