Next Generation Lipophilic Bisphosphonate Shows Antitumor Effect in Colorectal Cancer In Vitro and In Vivo
Next Generation Lipophilic Bisphosphonate Shows Antitumor Effect in Colorectal Cancer In Vitro and In Vivo
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DOI：
10.1007/s12253-019-00789-9
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发表时间：
2020-01-04
影响因子：
2.8
通讯作者：
Garay, Tamas
中科院分区：
文献类型：
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作者：
Baranyi, Marcell;Rittler, Dominika;Garay, Tamas
尽管双膦酸盐在许多肿瘤类型中具有体外抗肿瘤作用，但目前仅用于治疗骨质疏松症和骨转移。结直肠癌是第三种最常诊断的癌症类型，对携带RAS或RAF突变的病例缺乏靶向治疗。一种新的亲脂性双膦酸盐在肺癌模型中显示出良好的效果，但其对结直肠癌细胞的影响尚未得到过多的研究。研究了唑来膦酸（ZA）和一种亲脂双膦酸盐（BPH1222）对7株人结直肠癌细胞株的体外和体内抗肿瘤作用及其对ras相关信号的影响。此外，利用等基因细胞系研究了突变体KRAS对戊酰化抑制的依赖效应。两种双膦酸盐在体外以剂量依赖的方式降低细胞活力。这两种化合物通过增加S期或亚g1期或两者兼而有之的细胞比例，相似地改变了细胞周期分布。而BPH1222对球体生长的抑制作用高于ZA。有趣的是，我们发现在ZA或BPH1222处理后，Erk和S6蛋白的磷酸化水平发生了深刻的变化。此外，对突变的KRAS等基因模型系统的研究表明，这些药物也会干扰突变的KRAS蛋白。KRAS突变异种移植模型的体内实验也显示了双膦酸盐治疗的生长抑制潜力。我们的研究结果表明，亲脂性双膦酸盐可能扩展双膦酸盐药物的治疗范围，可以考虑作为结直肠癌的额外治疗方法。
Bisphosphonates, despite proven antitumor effect in vitro in many tumor types, are currently used only for treatment of osteoporosis and bone metastasis. Colorectal cancer is the third most commonly diagnosed type of cancer and lacks targeted therapy for RAS or RAF mutation carrying cases. A new lipophilic bisphosphonate showed promising results in lung cancer models, but their effect on colorectal cancer cells was not investigated excessively. Antitumor effects and impact on RAS-related signalization of zoledronic acid (ZA) and a lipophilic bisphosphonate (BPH1222) were investigated on 7 human colorectal cancer cell lines in vitro and in vivo. Furthermore, mutant KRAS dependent effect of prenylation inhibition was investigated using isogeneic cell lines. Both bisphosphonates reduced cell viability in vitro in a dose-dependent manner. Both compounds changed cell cycle distribution similarly by increasing the proportion of cells either in the S or in the subG1 phase or both. However, BPH1222 exerted higher inhibitory effect on spheroid growth than ZA. Interestingly, we found profound alterations in phosphorylation level of Erk and S6 proteins upon ZA or BPH1222 treatment. Furthermore, investigation of a mutant KRAS isogeneic model system suggests that the drugs interfere also with the mutant KRAS proteins. In vivo experiments with KRAS mutant xenograft model also revealed growth inhibitory potential of bisphosphonate treatment. Our results show that lipophilic bisphosphonates might extend the therapeutic spectrum of bisphosphonate drugs and could be considered as additional treatment approaches in colorectal cancer.