title: Ursolic acid and resveratrol synergize with chloroquine to reduce melanoma cell viability.
abstract: 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.
authors: 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.
authors: Jacob J
authors: JJ
authors: Junco
authors: Anna
authors: A
authors: Mancha-Ramirez
authors: Gunjan
authors: G
authors: Malik
authors: Sung-Jen
authors: SJ
authors: Wei
authors: Dae Joon
authors: DJ
authors: Kim
authors: Huiyun
authors: H
authors: Liang
authors: Thomas J
authors: TJ
authors: Slaga
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D002738:Chloroquine; D000077185:Resveratrol; D013267:Stilbenes; D014315:Triterpenes; D000097245:Ursolic Acid