Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells

Abstract

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.

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

“…Compared with their parental EOC cell lines, A2780-SP and SKOV3-SP cells exhibited CSC characteristics. A2780-SP cells have higher messenger RNA (mRNA) and protein levels of stemness markers than A2780 cells [ 15 , 22 ], and SKOV3-SP cells expressed higher mRNA levels of stemness markers than SKOV3 cells ( Figure S1A ). In addition, A2780-SP cells expressed higher mRNA levels of ERBB4 (HER4) [ 16 ], and SKOV3-SP cells expressed higher mRNA levels of ERBB2 (HER2) and ERBB4 (HER4) than their parent cells ( Figure S1B ).…”

“…AKT is phosphorylated downstream of PI3K signaling [ 32 , 33 ], and ERK phosphorylation is enhanced by overexpression of the ErbB4 receptor [ 16 , 34 ]. The overexpressed L/T-type calcium channels increase calcium flow into the cytoplasm, which drives phosphorylation of AKT and ERK through PI3K and MAPK signaling [ 15 , 35 ]. The phosphorylation of AKT and ERK stabilizes β-catenin, which translocates into the nucleus from the cytoplasm to increase transcription of CD133, NANOG, SOX2, and KLF4, thereby maintaining the stemness of ovarian CSCs ( Figure 5 D).…”

“…In previous studies, we used sphere-forming cells derived from A2780 and SKOV3 epithelial ovarian cancer cells (A2780-SP and SKOV3-SP cells), which have the characteristics of CSCs, to screen for drugs that target ovarian CSCs. Our screen identified four voltage-gated calcium channel blockers (CCBs; manidipine, lacidipine, lomerizine HCl, and benidipine HCl) and a pan-epithermal growth factor receptor (EGFR) inhibitor (poziotinib) that target ovarian CSCs [ 15 , 16 ]. The CCBs are approved by the United States (US) Food and Drug Administration as antihypertensive agents [ 17 ].…”

The Relationship Between Anti-Hypertensive Drugs and Cancer: Anxiety to be Resolved in Urgent

“…In 1984, Tsuruo et al ( Tsuruo, 1984 ) found that calcium regulators might increase the level of anti-tumor cells and reduce anti-tumor resistance by inhibiting the delivery of anti-tumor drugs from cancer cells. Recent studies have shown that CCBs reduce the ball formation, viability and proliferation of ovarian cancer stem cells (CSCs), and induce their apoptosis ( Lee et al, 2020 ). Moreover, recent studies have also suggested that the traditional diuretic spironolactone might increase the death and inhibit cell growth of cancer cells treated with gemcitabine and osimertinibe mainly by regulating the expression of the anti-apoptotic protein surviving ( Sanomachi et al, 2019 ).…”

Altered Organelle Calcium Transport in Ovarian Physiology and Cancer

“…On a similar note, Lee et al have tested four FDA-approved calcium channel blockers targeting ovarian cancer stem cells (CSCs). They found that these compounds not only decreased the expression of the antiapoptotic factors survivin, B-cell lymphoma 2 (Bcl-2), and myeloid cell leukemia 1 (Mcl-1), but also induced caspase activation, highlighting their potential use as anticancer agents [ 100 ].…”