Yan Tao, Li Hai-Ying, Wu Jian-Song, Niu Qiang, Duan Wei-Hong, Han Qing-Zeng, Ji Wang-Ming, Zhang Tao, Lv Wei
Department of Hepatobiliary Surgery, The General Hospital of The PLA Rocket Force, Beijing 100088, P.R. China.
Surgical Department, Qinghe County Central Hospital, Qinghe, Xingtai, Hebei 054800, P.R. China.
Oncol Lett. 2017 Nov;14(5):5400-5408. doi: 10.3892/ol.2017.6836. Epub 2017 Aug 28.
Pancreatic cancer rapidly acquires resistance to chemotherapy resulting in its being difficult to treat. Gemcitabine is the current clinical chemotherapy strategy; however, owing to gemcitabine resistance, it is only able to prolong the life of patients with pancreatic cancer for a limited number of months. Understanding the underlying molecular mechanisms of gemcitabine resistance and selecting a suitable combination of agents for the treatment of pancreatic cancer is required. Astaxanthin (ASX) is able to resensitize gemcitabine-resistant human pancreatic cancer cells (GR-HPCCs) to gemcitabine. ASX was identified to upregulate human equilibrative nucleoside transporter 1 (hENT1) and downregulate ribonucleoside diphosphate reductase (RRM) 1 and 2 to enhance gemcitabine-induced cell death in GR-HPCCs treated with gemcitabine, and also downregulates TWIST1 and ZEB1 to inhibit the gemcitabine-induced epithelial-mesenchymal transition (EMT) phenotype in GR-HPCCs and to mediate hENT1, RRM1 and RRM2. Furthermore, ASX acts through the hypoxia-inducible factor 1α/signal transducer and activator of transcription 3 signaling pathway to mediate TWIST1, ZEB1, hENT1, RRM1 and RRM2, regulating the gemcitabine-induced EMT phenotype and gemcitabine-induced cell death. Co-treatment with ASX and gemcitabine in a tumor xenograft model induced by GR-HPCCs supported the results. The results of the present study provide a novel therapeutic strategy for the treatment of gemcitabine-resistant pancreatic cancer.
胰腺癌会迅速对化疗产生耐药性，导致其难以治疗。吉西他滨是目前的临床化疗方案；然而，由于吉西他滨耐药性，它仅能将胰腺癌患者的生命延长有限的几个月。需要了解吉西他滨耐药的潜在分子机制，并选择合适的联合用药方案来治疗胰腺癌。虾青素（ASX）能够使耐吉西他滨的人胰腺癌细胞（GR-HPCCs）对吉西他滨重新敏感。已确定ASX可上调人平衡核苷转运体1（hENT1）并下调核糖核苷二磷酸还原酶（RRM）1和2，以增强吉西他滨诱导的GR-HPCCs细胞死亡，且还能下调TWIST1和ZEB1，以抑制吉西他滨诱导的GR-HPCCs上皮-间质转化（EMT）表型，并介导hENT1、RRM1和RRM2。此外，ASX通过缺氧诱导因子1α/信号转导和转录激活因子3信号通路发挥作用，以介导TWIST1、ZEB1、hENT1、RRM1和RRM2，调节吉西他滨诱导的EMT表型和吉西他滨诱导的细胞死亡。在由GR-HPCCs诱导的肿瘤异种移植模型中，ASX与吉西他滨联合治疗支持了这些结果。本研究结果为耐吉西他滨胰腺癌的治疗提供了一种新的治疗策略。
