Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Cancer Chemother Pharmacol. 2023 May;91(5):389-400. doi: 10.1007/s00280-023-04529-4. Epub 2023 Mar 30.
The mitochondria-targeted antioxidants (MTAs) are known to offer protection against mitochondrial oxidative stress. The recent evidences support their role in mitigating oxidative stress-induced diseases, including cancer. Therefore, this study investigated cardioprotective potential of mito-TEMPO against 5-FU-induced cardiotoxicity.
Mito-TEMPO was administered to male BALB/C mice (intraperitoneally, 0.1 mg/kg b.w. for 7 days) followed by intraperitoneal administration of 5- FU (12 mg/kg b.w. for 4 days). During this period, mito-TEMPO treatment was also continued. The cardioprotective potential of mito-TEMPO was assessed by evaluating cardiac injury markers, extent of non-viable myocardium and histopathological alterations. Mitochondrial functional status and mitochondrial oxidative stress were assessed in cardiac tissue. 8-OHdG expression and apoptotic cell death were assessed using immunohistochemical techniques.
The level of cardiac injury markers CK-MB and AST were significantly (P ≤ 0.05) decreased in mito-TEMPO pre-protected group which was further reflected in histopathology as decrease in the percentage of non-viable myocardial tissue, disorganization, and loss of myofibrils. Mito-TEMPO ameliorated mtROS, mtLPO and conserved mitochondrial membrane potential. Further, it had significantly (P ≤ 0.05) improved the activity of mitochondrial complexes and mitochondrial enzymes. A significant (P ≤ 0.05) increase in the level of mtGSH, activity of mitochondrial glutathione reductase, glutathione peroxidase, and mitochondrial superoxide dismutase was observed. A decreased expression of 8-OHdG and reduced apoptotic cell death were observed in mito-TEMPO pre-protected group.
Mito-TEMPO effectively mitigated 5-FU-induced cardiotoxicity by modulating mitochondrial oxidative stress, hence may serve as a protective agent/adjuvant in 5-FU-based combinatorial chemotherapy.
已知靶向线粒体的抗氧化剂 (MTA) 可提供针对线粒体氧化应激的保护。最近的证据支持其在减轻氧化应激诱导的疾病（包括癌症）中的作用。因此，本研究调查了 mito-TEMPO 对 5-FU 诱导的心脏毒性的心脏保护潜力。
雄性 BALB/C 小鼠（腹腔内，0.1mg/kg bw，7 天）给予 mito-TEMPO，随后腹腔内给予 5-FU（12mg/kg bw，4 天）。在此期间，继续给予 mito-TEMPO 治疗。通过评估心脏损伤标志物、非存活心肌的程度和组织病理学改变来评估 mito-TEMPO 的心脏保护潜力。评估心脏组织中的线粒体功能状态和线粒体氧化应激。使用免疫组织化学技术评估 8-OHdG 表达和凋亡细胞死亡。
mito-TEMPO 预先保护组的心脏损伤标志物 CK-MB 和 AST 水平显著降低（P≤0.05），这在组织病理学上进一步反映为非存活心肌组织、组织结构紊乱和肌原纤维丢失的百分比降低。mito-TEMPO 减轻了 mtROS、mtLPO 和线粒体膜电位。此外，它还显著改善了线粒体复合物和线粒体酶的活性（P≤0.05）。观察到 mtGSH 水平、线粒体谷胱甘肽还原酶、谷胱甘肽过氧化物酶和线粒体超氧化物歧化酶的活性显著增加（P≤0.05）。mito-TEMPO 预先保护组观察到 8-OHdG 表达减少和凋亡细胞死亡减少。
mito-TEMPO 通过调节线粒体氧化应激有效减轻 5-FU 诱导的心脏毒性，因此可能作为基于 5-FU 的联合化疗中的保护剂/佐剂。
