Title:The Curcumin Analog EF24 is Highly Active Against Chemotherapy- Resistant Melanoma Cells
Volume: 21
Issue: 7
Author(s): Yonghan He*, Wen Li, Junling Zhang, Yang Yang, Yawei Qian and Daohong Zhou
Affiliation:
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610,United States
Keywords:
Bcl-2, EF24, IAPs, malignant melanoma, NF-κB, unfolded protein response.
Abstract:
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.
