Spironolactone inhibits the growth of cancer stem cells by impairing DNA damage response

Ayala Gold, Lital Eini, Malka Nissim-Rafinia, Ruth Viner, Shlomit Ezer, Keren Erez, Nasma Aqaqe, Rotem Hanania, Michael Milyavsky, Eran Meshorer, Michal Goldberg

Research output: Contribution to journalArticlepeer-review

Abstract

The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.

Original languageEnglish
Pages (from-to)3103-3118
Number of pages16
JournalOncogene
Volume38
Issue number17
DOIs
StatePublished - 25 Apr 2019

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