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
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DOI：
10.3390/cancers11101550
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发表时间：
2019-10-01
期刊：
影响因子：
5.2
通讯作者：
Yamamoto, Masahiro
中科院分区：
文献类型：
--
作者：
Sanomachi, Tomomi;Suzuki, Shuhei;Yamamoto, Masahiro
螺内酯是一种经典的利尿药，用于治疗癌症患者的肿瘤相关并发症。最近报道螺内酯通过抑制DNA损伤修复发挥抗癌作用。然而，目前尚不清楚螺内酯是否与非DNA损伤性抗癌药物（如吉西他滨和表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI））发挥联合作用。使用肺癌、胰腺癌和胶质母细胞瘤的癌细胞，通过细胞活力测定在体外检查螺内酯与吉西他滨和奥希替尼（第三代EGFR-TKI）的联合作用。为了阐明潜在的机制，我们研究了由螺内酯诱导的抗凋亡蛋白生存素的改变，以及由生存素抑制剂YM 155和siRNA抑制生存素的化学增敏作用。我们还检查了小鼠异种移植模型中的组合效应。获得的结果显示，螺内酯增加了吉西他滨和奥希替尼引起的细胞死亡和细胞生长抑制。螺内酯还降低了这些细胞中生存素的表达，以及生存素对吉西他滨和奥希替尼敏感细胞的药理学和遗传抑制。该组合还显著抑制肿瘤生长，在体内没有明显的不良反应。总之，螺内酯是一种安全的候选药物，与非DNA损伤药物（如吉西他滨和奥希替尼）联合使用时发挥抗癌作用，最有可能是通过抑制生存素。
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.