School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China School of Basic Medical Sciences & Forensic Medicine Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
Int J Biol Sci. 2022 May 21;18(9):3747-3761. doi: 10.7150/ijbs.70679. eCollection 2022.
Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一，但成功治疗仍然是一个挑战。在这项研究中，我们发现广谱抗真菌药物酮康唑（OXI）对 CRC 具有一定的抗肿瘤作用。自噬阻滞和随后的细胞凋亡是 OXI 抑制 CRC 细胞生长的关键事件。在机制上，OXI 通过下调抗氧化酶过氧化物酶 2（PRDX2）的蛋白水平来解毒活性氧（ROS），通过抑制 Akt/mTOR 通路和 RAB7A 介导的自噬体与溶酶体融合来启动自噬，导致自噬体的极度积累和随后的 CRC 细胞生长抑制。一致地，干扰自噬或过表达 PRDX2 显著阻碍 OXI 诱导的 CRC 细胞生长抑制。此外，OXI 联合奥沙利铂（CRC 治疗的主要药物）可实现抗肿瘤作用的改善。总之，我们的研究结果为 OXI 诱导的自噬阻滞和对 CRC 细胞的生长抑制作用提供了新的机制见解，并提示 OXI 在 CRC 治疗中具有有前途的治疗作用。
