Background: Malignant melanoma (MM) is an aggressive type of skin cancer with a poor prognosis, because MM cells are characterized by unresponsiveness to chemotherapy.
Objective: In this study, we evaluated the effectiveness of several curcumin analogs on four MM cell lines (SK-MEL-28, MeWo, A-375, and CHL-1) and explored their underlying mechanisms of action.
Methods: Cell viability was measured by a Tetrazolium-based MTS assay. Cell apoptosis, reactive oxygen species (ROS), and cell cycle were assayed by flow cytometry. Protein levels were assayed by western blotting.
Results: MM cells are quite resistant to the conventional chemotherapeutics cisplatin and dacarbazine, and the targeted therapy drug vemurafinib. Among the curcumin analogs, EF24 is the most potent compound against the resistant MM cells. EF24 dose and time-dependently reduced the viability of MM cells by inducing apoptosis. Although EF24 did not increase the production of reactive oxygen species (ROS), it upregulated the endoplasmic reticulum (ER) stress marker BiP, but downregulated the unfolded protein response (UPR) signaling. Moreover, treatment of MM cells with EF24 downregulated the expression of the anti-apoptotic protein Bcl-2, as well as the inhibitor of apoptosis proteins (IAPs) XIAP, cIAP1, and Birc7, which are known to protect MM cells from apoptosis. The downregulation of Bcl-2 and IAP expression by EF24 was associated with the inhibition of the NF-κB pathway.
Conclusion: These findings demonstrate that EF24 is a potent anti-MM agent. The anti-MM effect is likely mediated by the suppression of UPR and the NF-κB pathway.
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