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

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/?-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.

SUBMITTER: Lee H

PROVIDER: S-EPMC7583017 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Lee Heejin H Kim Jun Woo JW Lee Dong-Seok DS Min Sang-Hyun SH

International journal of molecular sciences 20201006 19

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 ...[more]

PMID: 33036254

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Project description:Gastric cancer (GC), one of the types of tumor most prone to malignancy, is characterized by high lethality. Numerous molecular mediators of GC have been identified, including transcription factors, signaling molecules and non-coding RNAs. Recently, inhibition of angiogenesis has emerged as a potential strategy for GC therapy. In the present study, the levels of vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor-? (PPAR?) and miR-21 in GC patients and individuals without cancer, and the correlation between VEGF and miR-21, and PPAR? and miR-21 expression were analyzed. In addition, the GC MKN45 cell line was treated with apatinib (a tyrosine kinase inhibitor) and aspirin (an activator of the transcription factor, PPAR?) to investigate the effects of these compounds on tumorigenesis. Furthermore, the present study attempted to elucidate the molecular mechanisms of alteration of GC tumorigenesis by aspirin and apatinib. The results of the current study demonstrated that there was a higher expression of VEGF and miR-21 in GC tissues compared with that in morphologically adjacent normal tissues whereas PPAR? expression was decreased. These results were confirmed in vitro, as treatment of MKN45 cells with VEGF resulted in a significant increase in miR-21 expression and a significant reduction in PPAR? protein expression. Furthermore, the inhibitory effects of VEGF on PPAR? mRNA and protein expression were demonstrated to be mediated by miR-21. Suppression of PPAR? protein expression attenuated the inhibitory effects of miR-21 on the level of PPAR? mRNA, thereby enhancing tumorigenesis in gastric cancer. Treatment of MKN45 cells with aspirin reduced the levels of phosphorylated AKT by activating PPAR?, whereas treatment with apatinib inhibited the phosphorylation of vascular endothelial growth factor receptor 2 and phosphoinositide-3 kinase in MKN45 cells. Finally, treatment of MKN45 cells with apatinib and aspirin suppressed tumorigenesis by inhibiting cell proliferation, migration, invasion and colony formation. Taken together, the results of the present study indicate that treatment with a combination of aspirin and apatinib may be a potential therapeutic strategy for GC treatment.

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

Publications

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

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