Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, 200065, People's Republic of China.
Department of Surgery, Putuo Central Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People's Republic of China.
Cancer Chemother Pharmacol. 2020 Aug;86(2):221-232. doi: 10.1007/s00280-020-04100-5. Epub 2020 Jul 11.
Gemcitabine (GEM), as an anti-metabolic nucleoside analog, has been shown to have anticancer effects in various tumors, but its chemotherapy resistance is still an important factor leading to poor prognosis of cancer patient. A large number of studies in recent years have shown that autophagy plays an important role in the chemotherapy sensitivity of many tumors, including pancreatic, non-small cell lung, and bladder cancer. However, whether GEM causes autophagy in gallbladder cancer (GBC) and whether it is related to chemotherapy resistance is unknown. In the present study, we demonstrated that GEM induced apoptosis and protective autophagy in GBC cells, which may be related to the AKT/mTOR signaling pathway, and GEM in combination with autophagy inhibitor chloroquine can strengthen the cytotoxic effect of GEM on GBC in vitro and in vivo. These findings showed that both autophagy and AKT/mTOR signals were engaged in GBC cell death evoked by GEM, GBC patients might benefit from this new treatment strategy, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.
吉西他滨（GEM）作为一种抗代谢核苷类似物，已被证明在多种肿瘤中具有抗癌作用，但化疗耐药仍然是导致癌症患者预后不良的重要因素。近年来大量研究表明，自噬在包括胰腺癌、非小细胞肺癌和膀胱癌在内的许多肿瘤的化疗敏感性中发挥着重要作用。然而，GEM 是否会引起胆囊癌（GBC）中的自噬，以及它是否与化疗耐药有关尚不清楚。在本研究中，我们证明 GEM 诱导 GBC 细胞凋亡和保护性自噬，这可能与 AKT/mTOR 信号通路有关，并且 GEM 与自噬抑制剂氯喹联合使用可以增强 GEM 在体外和体内对 GBC 的细胞毒性作用。这些发现表明，自噬和 AKT/mTOR 信号都参与了 GEM 诱导的 GBC 细胞死亡，GBC 患者可能从这种新的治疗策略中获益，并且分子靶向治疗联合自噬抑制剂有望作为一种治疗改善。
