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Ursolic acid and resveratrol synergize with chloroquine to reduce melanoma cell viability

Junco, Jacob J.a; Mancha-Ramirez, Annaa; Malik, Gunjana; Wei, Sung-Jena,b; Kim, Dae Joona,b; Liang, Huiyuna; Slaga, Thomas J.a

doi: 10.1097/CMR.0000000000000137

Malignant melanoma is associated with a 5-year survival rate of less than 20% once metastasized. Malignant melanoma cells exhibit increased levels of autophagy, a process of intracellular digestion that allows cells to survive various stresses including chemotherapies, resulting in reduced patient survival. Autophagy can be inhibited by chemicals like chloroquine (CQ), which prevents fusion of autophagosomes to lysosomes, resulting in autophagosome accumulation in most systems. Here, we describe how tested CQ to see whether it could sensitize B16F10 metastatic mouse melanoma cells to the anticancer activities of the natural compounds ursolic acid (UA) and resveratrol (RES). CQ with UA or RES strongly and synergistically reduced the viability of B16F10 mouse melanoma and A375 human melanoma cells. Surprisingly, flow cytometry of acridine orange-stained cells showed that UA or RES in combination with CQ significantly reduced autophagosome levels. Western blotting analysis revealed that CQ plus UA or RES paradoxically increased LC3II, indicative of autophagosome accumulation. In addition, CQ plus RES synergistically decreased the levels of both autophagy initiator beclin-1 and autophagy supporter p62. These results indicate that CQ with UA or RES strongly and synergistically reduces the viability of B16F10 and A375 melanoma cells. However, studies on B16F10 cells have shown that the synergistic effect was not mediated by inhibition of autophagy induced by UA or RES. These compounds are well-tolerated in humans, and CQ has shown promise as an adjuvant therapy. These combinations may be valuable treatment strategies for melanoma.

aDepartment of Pharmacology

bEdinburg Regional Academic Health Center, Medical Research Division, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Correspondence to Thomas J. Slaga, PhD, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA Tel: +1 210 567 4231; fax: +1 210 567 4300; e-mail:

Received June 24, 2013

Accepted December 12, 2014

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