Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study
Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study
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DOI：
10.1248/bpb.b15-00746
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发表时间：
2016-08-01
影响因子：
2
通讯作者：
Shimazoe, Takao
中科院分区：
文献类型：
--
作者：
Elsayed, Mahitab;Kobayashi, Daisuke;Shimazoe, Takao
已知双膦酸盐和他汀类药物对不同类型的癌细胞具有抗肿瘤活性。在本研究中，我们研究了二磷酸盐唑来膦酸(ZOL)和他汀类药物氟伐他汀(Flu)在体外对两种类型的人胰腺癌细胞Mia Paca-2和Suit-2的抗增殖作用。用WST-8细胞增殖实验评价ZOL和Flu单独及联合作用对胰腺癌细胞的抗增殖作用。在这项研究中，我们证明了当两种药物在两种细胞系中联合使用时，具有很强的协同抗增殖作用。此外，我们还研究了甲氧丙酮酸途径产物法尼基焦磷酸(FPP)和香叶基焦磷酸(GGPP)抑制这种协同作用的分子机制。此外，我们的目的是确定ZOL和Flu联合使用对RhoA和Ras鸟苷5‘-三磷酸(GTP)蛋白的影响。这种结合诱导了RhoA和未戊烯基化的RAS的显著积累。GGPP和FPP逆转了这两种蛋白质数量的增加。这些结果表明，联合处理通过抑制香叶基香叶化和/或法尼化而损害了RhoA和Ras信号通路。这项研究为联合使用ZOL和流感治疗胰腺癌提供了一种潜在的有效方法。
Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5'-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU.