Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy.
Medical Oncology Unit, ASST del Garda, 25015 Desenzano del Garda, Italy.
Int J Mol Sci. 2021 Jul 30;22(15):8230. doi: 10.3390/ijms22158230.
Cholangiocarcinoma is the first most common cancer of the biliary tract. To date, surgical resection is the only potentially curative option, but it is possible only for a limited percentage of patients, and in any case survival rate is quite low. Moreover, cholangiocarcinoma is often chemotherapy-resistant, and the only drug with a significant benefit for patient's survival is Gemcitabine. It is necessary to find new drugs or combination therapies to treat nonresectable cholangiocarcinoma and improve the overall survival rate of patients. In this work, we evaluate in vitro the antitumoral effects of Rigosertib, a multi-kinase inhibitor in clinical development, against cholangiocarcinoma EGI-1 cell lines. Rigosertib impairs EGI-1 cell viability in a dose- and time-dependent manner, reversibility is dose-dependent, and significant morphological and nuclear alterations occur. Moreover, Rigosertib induces the arrest of the cell cycle in the G2/M phase, increases autophagy, and inhibits proteasome, cell migration, and invasion. Lastly, Rigosertib shows to be a stronger radiosensitizer than Gemcitabine and 5-Fluorouracil. In conclusion, Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.
胆管癌是胆道系统最常见的第一大癌症。迄今为止，手术切除是唯一有潜在治愈可能的方法，但它只适用于一小部分患者，而且无论如何，生存率都相当低。此外，胆管癌通常对化疗有耐药性，唯一能显著提高患者生存率的药物是吉西他滨。有必要寻找新的药物或联合疗法来治疗不可切除的胆管癌，提高患者的总生存率。在这项工作中，我们评估了多激酶抑制剂里戈西替尼（一种处于临床开发阶段的药物）对胆管癌细胞系 EGI-1 的体外抗肿瘤作用。里戈西替尼以剂量和时间依赖的方式损害 EGI-1 细胞活力，其可逆性与剂量相关，并且会引起明显的形态和核改变。此外，里戈西替尼诱导细胞周期在 G2/M 期停滞，增加自噬，并抑制蛋白酶体、细胞迁移和侵袭。最后，里戈西替尼显示出比吉西他滨和 5-氟尿嘧啶更强的放射增敏作用。总之，里戈西替尼单独或联合放疗可能是一种潜在的治疗选择，适用于不可切除的胆管癌患者。
