Chen Kuan-Chou, Chen Chang-Rong, Chen Chang-Yu, Peng Chiung-Chi, Peng Robert Y
Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xing St., Sin-Yi District, Taipei 11031, Taiwan.
Department of Urology, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan.
J Clin Med. 2021 Dec 27;11(1):135. doi: 10.3390/jcm11010135.
Bicalutamide (Bic) is an androgen deprivation therapy (ADT) for treating prostate cancer, while ADT is potentially associated with acute kidney injury. Previously, we recognized Bic induced renal mitochondria dysfunction in vitro and in vivo via the ROS -HIF1α pathway. Whether OXPHOS complex, as well as mitochondrial dynamics, can be influenced by Bic via modulation of peroxisome proliferator-activated receptor coactivator 1α (PGC1α), NADPH oxidase 4 (Nox4), mitofusins 1/2 (MFN 1/2), optic atrophy 1 (OPA1), and sirtuins (SIRTs) has not been documented. Renal mesangial cell line was treated with Bic (30~60 μM) for the indicated time. SIRTs, complex I, mitochondrial dynamics- and oxidative stress-related proteins were analyzed. Bic dose-dependently reduced mitochondrial potential, but dose- and time-dependently suppressed translocase of the outer mitochondrial membrane member 20 (Tomm 20), complex I activity. Nox4 and glutathione lead to decreased NAD/NADH ratio, with upregulated superoxide dismutase 2. SIRT1 was initially stimulated and then suppressed, while SIRT3 was time- and dose-dependently downregulated. PGC1α, MFN2, and OPA1 were all upregulated, with MFN1 and pro-fission dynamin-related protein I downregulated. Bic exhibits potential to damage mitochondria via destroying complex I, complex I activity, and mitochondrial dynamics. Long-term treatment with Bic should be carefully followed up.
比卡鲁胺（Bic）是一种用于治疗前列腺癌的雄激素剥夺疗法（ADT），而ADT可能与急性肾损伤有关。此前，我们发现Bic在体外和体内通过ROS-HIF1α途径诱导肾线粒体功能障碍。OXPHOS复合体以及线粒体动力学是否会受到Bic通过调节过氧化物酶体增殖物激活受体辅激活因子1α（PGC1α）、NADPH氧化酶4（Nox4）、线粒体融合蛋白1/2（MFN 1/2）、视神经萎缩蛋白1（OPA1）和沉默调节蛋白（SIRTs）的影响，尚未见报道。用Bic（30~60μM）处理肾系膜细胞系指定时间。分析SIRTs、复合体I、线粒体动力学和氧化应激相关蛋白。Bic剂量依赖性地降低线粒体电位，但剂量和时间依赖性地抑制线粒体外膜转位酶20（Tomm 20）、复合体I活性。Nox4和谷胱甘肽导致NAD/NADH比值降低，超氧化物歧化酶2上调。SIRT1最初受到刺激，然后受到抑制，而SIRT3则呈时间和剂量依赖性下调。PGC1α、MFN2和OPA1均上调，MFN1和促分裂动力蛋白相关蛋白I下调。Bic具有通过破坏复合体I、复合体I活性和线粒体动力学来损伤线粒体的潜力。长期使用Bic治疗应仔细随访。
