Plumbagin Elicits Cell-Specific Cytotoxic Effects and Metabolic Responses in Melanoma Cells
Keywords：cytotoxic effect; melanoma; metabolism; mitochondria; plumbagin; reactive oxygen species
关键词：细胞毒作用； 黑色素瘤; 代谢; 线粒体； 铅素; 活性氧
细胞类型：内皮细胞；上皮细胞；间皮细胞
作者：Zhang H, Zhang A, Gupte AA, Hamilton DJ
出版期刊：《Pharmaceutics》 2021/5/12
Abstract：
Melanoma is one of the most malignant skin cancers that require comprehensive therapies, including chemotherapy. A plant-derived drug, plumbagin (PLB), exhibits an anticancer property in several cancers. We compared the cytotoxic and metabolic roles of PLB in A375 and SK-MEL-28 cells, each with different aggressiveness. In our results, they were observed to have distinctive mitochondrial respiratory functions. The primary reactive oxygen species (ROS) source of A375 can be robustly attenuated by cell membrane permeabilization. A375 cell viability and proliferation, migration, and apoptosis induction are more sensitive to PLB treatment. PLB induced metabolic alternations in SK-MEL-28 cells, which included increasing mitochondrial oxidative phosphorylation (OXPHOS), mitochondrial ATP production, and mitochondrial mass. Decreasing mitochondrial OXPHOS and total ATP production with elevated mitochondrial membrane potential (MMP) were observed in PLB-induced A375 cells. PLB also induced ROS production and increased proton leak and non-mitochondria respiration in both cells. This study reveals the relationship between metabolism and cytotoxic effects of PLB in melanoma. PLB displays stronger cytotoxic effects on A375 cells, which exhibit lower respiratory function than SK-MEL-28 cells with higher respiratory function, and triggers cell-specific metabolic changes in accordance with its cytotoxic effects. These findings indicate that PLB might serve as a promising anticancer drug, targeting metabolism.
文章摘要：
黑色素瘤是最恶性的皮肤癌之一，需要综合治疗，包括化疗。一种植物源性药物白铅素 (PLB) 在几种癌症中表现出抗癌特性。我们比较了 PLB 在 A375 和 SK-MEL-28 细胞中的细胞毒性和代谢作用，每种细胞都具有不同的侵袭性。在我们的结果中，观察到它们具有独特的线粒体呼吸功能。 A375 的主要活性氧 (ROS) 来源可通过细胞膜透化作用显着减弱。 A375 细胞活力和增殖、迁移和细胞凋亡诱导对 PLB 治疗更敏感。 PLB 在 SK-MEL-28 细胞中诱导代谢改变，包括增加线粒体氧化磷酸化 (OXPHOS)、线粒体 ATP 产生和线粒体质量。在 PLB 诱导的 A375 细胞中观察到线粒体 OXPHOS 和总 ATP 产生减少，线粒体膜电位 (MMP) 升高。 PLB 还诱导 ROS 产生并增加两个细胞中的质子泄漏和非线粒体呼吸。本研究揭示了 PLB 在黑色素瘤中的代谢和细胞毒作用之间的关系。 PLB对A375细胞表现出更强的细胞毒作用，其呼吸功能低于呼吸功能较高的SK-MEL-28细胞，并根据其细胞毒作用触发细胞特异性代谢变化。这些发现表明，PLB 可能作为一种有前途的抗癌药物，靶向代谢。
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