Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States; Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
Aix Marseille Univ, CNRS, ICR, UMR 7273, Marseille 13013, France.
Cancer Treat Res Commun. 2020;25:100210. doi: 10.1016/j.ctarc.2020.100210. Epub 2020 Sep 17.
Melanoma is an aggressive form of skin cancer for which there are no effective drugs for prolonged treatment. The existing kinase inhibitor antiglycolytic drugs (B-Raf serine/threonine kinase or BRAF inhibitors) are effective for a short time followed by a rapid onset of drug resistance.
Here, we show that a mitochondria-targeted analog of magnolol, Mito-magnolol (Mito-MGN), inhibits oxidative phosphorylation (OXPHOS) and proliferation of melanoma cells more potently than untargeted magnolol. Mito-MGN also inhibited tumor growth in murine melanoma xenografts. Mito-MGN decreased mitochondrial membrane potential and modulated energetic and mitophagy signaling proteins.
Results indicate that Mito-MGN is significantly more potent than the FDA-approved OXPHOS inhibitor in inhibiting proliferation of melanoma cells.
These findings have implications in the treatment of melanomas with enhanced OXPHOS status due to metabolic reprogramming or drug resistance.
黑色素瘤是一种侵袭性皮肤癌，目前尚无有效的长期治疗药物。现有的激酶抑制剂抗糖酵解药物（B-Raf 丝氨酸/苏氨酸激酶或 BRAF 抑制剂）在短时间内有效，但随后迅速产生耐药性。
在这里，我们发现姜黄素的一种线粒体靶向类似物，Mito-magnolol（Mito-MGN），比非靶向姜黄素更有效地抑制黑色素瘤细胞的氧化磷酸化（OXPHOS）和增殖。Mito-MGN 还抑制了小鼠黑色素瘤异种移植瘤的生长。Mito-MGN 降低了线粒体膜电位，并调节了能量和自噬信号蛋白。
结果表明，Mito-MGN 比 FDA 批准的 OXPHOS 抑制剂更有效地抑制黑色素瘤细胞的增殖。
这些发现对代谢重编程或耐药性导致 OXPHOS 状态增强的黑色素瘤的治疗具有重要意义。
