Dong-Seok Lee

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

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.

Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells

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.

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.