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Oncogene. 2019 Apr;38(17):3103-3118. doi: 10.1038/s41388-018-0654-9. Epub 2019 Jan 8.

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

Author information

1
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel.
2
The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel.
3
Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel.
4
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel. eran.meshorer@mail.huji.ac.il.
5
The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel. eran.meshorer@mail.huji.ac.il.
6
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 9190401, Israel. goldbergm@mail.huji.ac.il.

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.

PMID:
30622338
DOI:
10.1038/s41388-018-0654-9
[Indexed for MEDLINE]

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