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

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

doi:10.1038/s41388-018-0654-9

Cited by 30 publications

(25 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are several sources of chemoresistance to cancer including alterations to drug transporters, the suppression of apoptosis, mitochondrial alterations, the promotion of DNA damage repair, autophagy, epithelial-mesenchymal transition, and CSCs [2,3,4,5]. Previous studies reported that spironolactone inhibits DNA repair and chemosensitizes cancer cells to DNA-damaging reagents, such as cisplatin [39,40,41]. In the present study, we revealed that spironolactone chemosensitized cancer cells to gemcitabine and osimertinib.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, spironolactone is a well-tolerated drug even in patients with cancer. Recent studies reported that spironolactone exerts anticancer effects by suppressing DNA damage repair and acts as a chemosensitizer in combination with DNA-damaging reagents, such as cisplatin [39,40,41]. Therefore, spironolactone is a good candidate drug for cancer therapy from the perspective of drug repositioning.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Sanomachi

Togashi

Sugai

et al. 2019

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sanomachi

Togashi

Sugai

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…377 They also identified that spironolactone could influence DNA doublestrand break repair in cancer stem cells. 378 Interestingly, Guillotin et al showed another diuretic drug, triamterene, was active against DNA mismatch repair-deficient tumors. They reported that triamterene increased reactive oxygen species (ROS)-mediated DNA double strand breaks by regulating folate synthesis enzyme and thymidylate synthase.…”

Section: Non-oncology Drugs In Drug Repurposingmentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

364

315

View full text Add to dashboard Cite

Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

show abstract

“…In addition, Mill et al [42] revealed that SP inhibited the proliferation of cardiac collagen after myocardial infarction. Gold et al [43] noticed that SP could induce apoptosis and therefore inhibited the progression of cancer stem cells. Given this information, SP might prevent the proliferation of PASMCs via downregulating the expressions of AQP1 and β-catenin in PAH status.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Contributed to Pulmonary Arterial Hypertension Development via Stimulating Aquaporin Expression and Pulmonary Arterial Smooth Muscle Cells Proliferation

Wang

Zhong

et al. 2020

Pharmacology

View full text Add to dashboard Cite

Introduction and Objective: The regulatory network of aquaporin (AQP) 1 and renin-angiotensin-aldosterone (ALDO) system are not quite clear in pulmonary arterial hypertension (PAH). Thus, we explored the role of AQP1, ALDO and spirolactone (SP) in the PAH animal model and pulmonary arterial smooth muscle cells (PASMCs). Method: PAH rat model was established by monocrotaline (MCT) via intraperitoneal in SD rat. Hemodynamic measurement was conducted via the external jugular vein cannula. PASMCs were extracted from normal SD rat and cultured in SmGM medium. α-Actin expression was identified by immunocytochemistry. Protein levels were assessed by Western blot. Cell viability was assayed using the MTT method. Apoptosis rate was evaluated by flow cytometry. ALDO level was measured by ELISA. Result: SP decreased AQP1 and β-catenin expressions in PAH rat model induced successfully by MCT. Moreover, ALDO increased AQP1 expression and cell viability in PASMCs, which were extracted from rat and identified by α-actin expression. AQP1 downregulation decreased β-catenin expression, and SP lowered AQP1 and β-catenin expressions elevated by ALDO in PASMCs. SP offset ALDO's effect on the upregulation of cell viability as well as AQP1 and β-catenin expressions in PASMCs. In addition, AQP1 downregulation and SP have a negative effect on Ki-67 and proliferating cell nuclear antigen expressions as well as cell viability after ALDO treatment in PASMCs. Conclusion: ALDO might contribute to PAH development via stimulating AQP1 expression and PASMCs proliferation. However, SP could be considered an effective drug regulating PASMCs proliferation through modulating AQP1 and β-catenin expressions in PAH.

show abstract

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

Cited by 30 publications

References 38 publications

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

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

Overcoming cancer therapeutic bottleneck by drug repurposing

Aldosterone Contributed to Pulmonary Arterial Hypertension Development via Stimulating Aquaporin Expression and Pulmonary Arterial Smooth Muscle Cells Proliferation

Contact Info

Product

Resources

About