Mitochondria-targeted magnolol inhibits OXPHOS, proliferation, and tumor growth via modulation of energetics and autophagy in melanoma cells.
Mitochondria-targeted magnolol inhibits OXPHOS, proliferation, and tumor growth via modulation of energetics and autophagy in melanoma cells.
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DOI：
10.1016/j.ctarc.2020.100210
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发表时间：
2020
影响因子：
--
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
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作者：
Cheng G;Hardy M;Zielonka J;Weh K;Zielonka M;Boyle KA;Abu Eid M;McAllister D;Bennett B;Kresty LA;Dwinell MB;Kalyanaraman B
黑色素瘤是一种侵袭性皮肤癌，没有有效的药物可以长期治疗。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，随后迅速产生耐药性。在这里，我们发现，一种靶向线粒体的厚朴酚类似物 Mito-magnolol (Mito-MGN) 比非靶向厚朴酚更有效地抑制氧化磷酸化 (OXPHOS) 和黑色素瘤细胞的增殖。 Mito-MGN 还抑制小鼠黑色素瘤异种移植物中的肿瘤生长。 Mito-MGN 降低线粒体膜电位并调节能量和线粒体自噬信号蛋白。结果表明，Mito-MGN 在抑制黑色素瘤细胞增殖方面比 FDA 批准的 OXPHOS 抑制剂更有效。这些发现对于治疗由于代谢重编程或耐药性而导致 OXPHOS 状态增强的黑色素瘤具有重要意义。
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.