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.
Highlights
Cutaneous melanoma, mainly caused by exposure to ultraviolet light, is the most dangerous skin cancer
After using digitonin to permeabilize the cell membrane in the Oroboros machine, the basal mitochondria oxygen consumption rate (OCR) increased in both A375 and SK-MEL-28 cells since the substrates of the mitochondrial complex I (Cx I) and complex II (Cx II), including L-glutamate, L-malic, pyruvate, and succinate, along with adenosine diphosphate (ADP), entered the cells and were oxidized by mitochondria in the mitochondria respiration buffer (MiR05; Figure 1a,b)
Since some melanomas with the BRAFV600E mutation are prone to become resistant to targeted inhibitors and therapeutic chemicals [18], new targets and substances are required in melanoma treatment
Summary
Mainly caused by exposure to ultraviolet light, is the most dangerous skin cancer. It accounts for 1% of skin cancer diagnoses but results in 90% of deaths from all skin cancers [1]. Surgery is generally considered a typical treatment for localized melanoma. With current evidence-based treatment, cutaneous melanoma with lymph node and distant metastasis is reported to have 66.2% and 27.3% five-year survival rates, respectively, in the United States compared with up to 99% survival for localized melanoma [3]. It is necessary to explore novel treatments in the management of melanomas with different aggressiveness. A375 and SK-MEL-28 are two human melanoma cell lines with the BRAF mutation at V600E; they were selected as representative models according to the Melanoma
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