2. Academic Validation
  3. 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

  • Cancers (Basel). 2019 Oct 14;11(10):1550. doi: 10.3390/cancers11101550.
Tomomi Sanomachi 1 2,  Shuhei Suzuki 3 4,  Keita Togashi 5 6,  Asuka Sugai 7,  Shizuka Seino 8,  Masashi Okada 9,  Takashi Yoshioka 10,  Chifumi Kitanaka 11 12,  Masahiro Yamamoto 13
Affiliations

Affiliations

  • 1 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. t-sanomachi@med.id.yamagata-u.ac.jp.
  • 2 Department of Clinical Oncology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. t-sanomachi@med.id.yamagata-u.ac.jp.
  • 3 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. s-suzuki@med.id.yamagata-u.ac.jp.
  • 4 Department of Clinical Oncology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. s-suzuki@med.id.yamagata-u.ac.jp.
  • 5 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. ke-togashi@med.id.yamagata-u.ac.jp.
  • 6 Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. ke-togashi@med.id.yamagata-u.ac.jp.
  • 7 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. s-asuka@med.id.yamagata-u.ac.jp.
  • 8 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. s.sizuka@med.id.yamagata-u.ac.jp.
  • 9 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. m-okada@med.id.yamagata-u.ac.jp.
  • 10 Department of Clinical Oncology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. ytakashi@med.id.yamagata-u.ac.jp.
  • 11 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. ckitanak@med.id.yamagata-u.ac.jp.
  • 12 Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. ckitanak@med.id.yamagata-u.ac.jp.
  • 13 Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. masahiro@med.id.yamagata-u.ac.jp.
PMID: 31614999 DOI: 10.3390/cancers11101550
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.

Keywords

cancer stem cells; drug resistance; osimertinib; spironolactone; survivin; xenograft.

Figures
Products