Minegaki T, Fukushima S, Morioka C, Takanashi H, Uno J, Tsuji S, Yamamoto S, Watanabe A, Tsujimoto M, Nishiguchi K
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
Dis Esophagus. 2016 Aug;29(6):656-62. doi: 10.1111/dote.12370. Epub 2015 Apr 20.
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers in Japan. Anticancer chemotherapy has been useful for ESCC treatment. However, therapeutic options are limited. Recently, bisphosphonates (BPs), which are osteoporosis drugs, have shown anticancer effects in several cancer cell lines, but the effects against ESCC cell lines are unknown. In this study, we examined the cytotoxic effects of BPs and their mechanisms of cytotoxicity in human ESCC cell lines. A first-generation BP (etidronate), two second-generation BPs (alendronate and pamidronate), and two third-generation BPs (risedronate and zoledronate) were used in this study. All BPs, except etidronate, were cytotoxic, as indicated by increased caspase-3/7 activity and numbers of Annexin-fluorescein isothiocyanate positive cells in ESCC cell lines. From cell cycle analysis, G0/G1-phase arrest was observed upon treatment with second- and third-generation BPs. In addition, Cyclin D1 protein expression levels were decreased by second- and third-generation BP treatment. Although squalene and trans, trans-farnesol minimally affected BP cytotoxicity, treatment with geranylgeraniol inhibited BP cytotoxicity almost completely. We concluded that second- and third-generation BPs are cytotoxic to ESCC cell lines as they induce apoptosis and inhibit the cell cycle through mevalonate pathway inhibition. Therefore, BP treatment may be a beneficial therapy in ESCC patients.
食管鳞状细胞癌（ESCC）是日本最恶性的癌症之一。抗癌化疗对ESCC治疗有效。然而，治疗选择有限。最近，作为骨质疏松症药物的双膦酸盐（BPs）在几种癌细胞系中显示出抗癌作用，但对ESCC细胞系的作用尚不清楚。在本研究中，我们研究了BPs对人ESCC细胞系的细胞毒性作用及其细胞毒性机制。本研究使用了第一代BP（依替膦酸）、两种第二代BP（阿仑膦酸和帕米膦酸）和两种第三代BP（利塞膦酸和唑来膦酸）。除依替膦酸外，所有BPs均具有细胞毒性，ESCC细胞系中caspase-3/7活性增加和膜联蛋白-异硫氰酸荧光素阳性细胞数量增加表明了这一点。通过细胞周期分析，在用第二代和第三代BPs处理后观察到G0/G1期阻滞。此外，第二代和第三代BP处理可降低细胞周期蛋白D1蛋白表达水平。虽然角鲨烯和反式，反式-法尼醇对BP细胞毒性影响最小，但香叶基香叶醇处理几乎完全抑制了BP细胞毒性。我们得出结论，第二代和第三代BPs对ESCC细胞系具有细胞毒性，因为它们通过抑制甲羟戊酸途径诱导细胞凋亡并抑制细胞周期。因此，BP治疗可能是ESCC患者的一种有益治疗方法。
