Department of Burn and Plastic Surgery, Shenzhen Longhua District Central Hospital, Affiliated Central Hospital of Shenzhen Longhua District, Guangdong Medical University, Shenzhen, Guangdong, China.
Department of Pharmacy, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong, China.
Oxid Med Cell Longev. 2021 Mar 18;2021:5510663. doi: 10.1155/2021/5510663. eCollection 2021.
Bladder cancer is one of the most commonly diagnosed cancers worldwide, especially in males. Current therapeutic interventions, including surgery, radiation therapy, chemotherapy, and immunotherapy, have not been able to improve the clinical outcome of bladder cancer patients with satisfaction. Recombinant human arginase (rhArg, BCT-100) is a novel agent with great anticancer effects on arginine-auxotrophic tumors. However, the effects of BCT-100 on bladder cancer remain unclear. In this study, the anticancer effects of BCT-100 were assessed using four bladder cancer cell lines (J82, SCaBER, T24, and 5637), while the effects were evaluated by establishing T24 nude mice xenograft models. Intracellular arginine level was observed to be sharply decreased followed by the onset of apoptotic events. Furthermore, BCT-100 was found to induce HO production and mitochondrial membrane depolarization, leading to the release of mitochondrial cytochrome c and Smac to the cytosol. Treatment with BCT was observed to upregulate the expression of LC3B and Becllin-1, but downregulate the expression of p62 in a time-dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of the AKT/mTOR pathway was suppressed in a time-dependent fashion in BCT-100-treated T24 cells. While N-acetyl-L-cysteine was shown to alleviate BCT-100-induced apoptosis and autophagy, chloroquine, MK-2206, and rapamycin were found to potentiate BCT-100-triggered apoptosis. Finally, BCT-100 was demonstrated to induce autophagy and apoptosis via the ROS-mediated AKT/mTOR signaling pathway in bladder cancer cells.
膀胱癌是全球最常见的癌症之一，尤其在男性中更为常见。目前的治疗干预措施，包括手术、放射治疗、化疗和免疫治疗，都未能改善膀胱癌患者的临床疗效。重组人精氨酸酶（rhArg，BCT-100）是一种新型药物，对精氨酸营养缺陷型肿瘤具有很好的抗癌作用。然而，BCT-100 对膀胱癌的作用尚不清楚。在这项研究中，使用四种膀胱癌细胞系（J82、SCaBER、T24 和 5637）评估了 BCT-100 的抗癌作用，并通过建立 T24 裸鼠异种移植模型来评估其作用。观察到细胞内精氨酸水平急剧下降，随后出现凋亡事件。此外，BCT-100 被发现诱导 HO 产生和线粒体膜去极化，导致线粒体细胞色素 c 和 Smac 释放到细胞质中。BCT 治疗观察到 LC3B 和 Becllin-1 的表达上调，而 p62 的表达下调呈时间依赖性。BCT-100 处理后也观察到自噬通量增加。此外，BCT-100 处理的 T24 细胞中 AKT/mTOR 通路的磷酸化呈时间依赖性抑制。虽然 N-乙酰-L-半胱氨酸被证明可以减轻 BCT-100 诱导的凋亡和自噬，但氯喹、MK-2206 和雷帕霉素被发现可以增强 BCT-100 触发的凋亡。最后，BCT-100 被证明通过 ROS 介导的 AKT/mTOR 信号通路在膀胱癌细胞中诱导自噬和凋亡。
