Spironolactone, a Classic Potassium-Sparing Diuretic, Reduces Survivin Expression and Chemosensitizes Cancer Cells to Non-DNA-Damaging Anticancer Drugs

Abstract

Spironolactone, a classical diuretic drug, is used to treat tumor-associated complications in cancer patients. Spironolactone was recently reported to exert anti-cancer effects by suppressing DNA damage repair. However, it currently remains unclear whether spironolactone exerts combinational effects with non-DNA-damaging anti-cancer drugs, such as gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Using the cancer cells of lung cancer, pancreatic cancer, and glioblastoma, the combinational effects of spironolactone with gemcitabine and osimertinib, a third-generation EGFR-TKI, were examined in vitro with cell viability assays. To elucidate the underlying mechanisms, we investigated alterations induced in survivin, an anti-apoptotic protein, by spironolactone as well as the chemosensitization effects of the suppression of survivin by YM155, an inhibitor of survivin, and siRNA. We also examined the combinational effects in a mouse xenograft model. The results obtained revealed that spironolactone augmented cell death and the suppression of cell growth by gemcitabine and osimertinib. Spironolactone also reduced the expression of survivin in these cells, and the pharmacological and genetic suppression of survivin sensitized cells to gemcitabine and osimertinib. This combination also significantly suppressed tumor growth without apparent adverse effects in vivo. In conclusion, spironolactone is a safe candidate drug that exerts anti-cancer effects in combination with non-DNA-damaging drugs, such as gemcitabine and osimertinib, most likely through the suppression of survivin.

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

“…Bortezomib also increases the sensitivity of GSC's to temozolomide in a dose and time-dependent manner by downregulating the FOXM1/survivin signaling pathway [245]. Diuretic, spironolactone sensitizes CSCs to Gemcitabine and Osimertinib [246]. Rho-assisted protein kinase inhibitors sensitize pancreatic CSCs to Gemcitabine by downregulating survivin [247].…”

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs

“…Importantly for OPALS, in 2019, experimental work again indicating the association between EGFR and the MR showed that spironolactone decreases GB cell survival and sensitized glioma cells to the EGFR inhibitor osimertinib [ 110 ].…”

“…Spironolactone was also shown to inhibit homologous repair of ds-DNA breaks [ 110 , 111 , 112 , 113 ]. The MOA of this is thought to be by spironolactone’s induction of xeroderma pigmentosum group B (XPB) protein degradation.…”

“…High throughput screening non-obvious drug combinations identified spironolactone as a synergistic partner drug to cisplatin and the related inhibition of homology directed DNA repair [ 114 , 115 ]. Although some studies have shown spironolactone exerts its anticancer effects by inhibiting DNA repair, thereby augmenting DNA-damaging drugs, a recent report demonstrated spironolactone’s synergy with non-genotoxic EGFR inhibitor osimertinib as well as to gemcitabine in both GB and in NSCLC cells [ 110 ].…”

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

“…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 ).…”