Differential Anti-Proliferative and Anti-Migratory Activities of Ursolic Acid, 3-O-Acetylursolic Acid and Their Combination Treatments with Quercetin on Melanoma Cells

Abstract

We evaluate how 3-acetylation modulates the in vitro activity of ursolic acid in melanoma cells alone or in combination treatments with quercetin. Anti-proliferative studies on A375 cells and adult human dermal fibroblasts included analyses on cell cycle distribution, caspase activity, phosphatidylserine translocation, cell morphology and Bax/Bcl-2 protein expression. Then, 2D and 3D migration of B16F10 cells were studied using scratch and Transwell assays, respectively. Ursolic acid and 3-O-acetylursolic acid have shown similar GI50 on A375 cells (26 µM vs. 32 µM, respectively) significantly increased both early and late apoptotic populations, activated caspases 3/7 (48–72 h), and enhanced Bax whilst attenuating Bcl-2 expression. Ursolic acid caused elevation of the sub-G1 population whilst its 3-acetyl derivative arrested cell cycle at S phase and induced strong morphological changes. Combination treatments showed that ursolic acid and quercetin act synergistically in migration assays but not against cell proliferation. In summary, 3-O-acetylursolic acid maintains the potency and overall apoptotic mechanism of the parent molecule with a more aggressive influence on the morphology of A375 melanoma cells but the 3-acetylation suppresses its anti-migratory properties. We also found that ursolic acid can act in synergy with quercetin to reduce cell migration.

Relationship between Maturity Stage, Triterpenoid Content and Cytotoxicity of Sorbus intermedia (EHRH.) PERS. Fruits – A Chemometric Approach

“…Also, AUA (isolated or semi‐synthesized) revealed cytotoxic and cytostatic activity in vitro towards various cancer cells, i. e ., HL‐60, BGC‐823, Hela, Bel‐7402, HepG2, AGS, HELF, K562, A375 [41–43] . More in‐depth study on this compound was conducted by Alqathama et al [44] . who assessed anti‐migratory and pro‐apoptotic properties of AUA against A375 cells.…”

Integrating network pharmacology with molecular docking to rationalize the ethnomedicinal use of Alchornea laxiflora (Benth.) Pax & K. Hoffm. for efficient treatment of depression

“…A similar or enhanced therapeutic potential has been reported with other structural ursolic acid derivatives such as amides, ester, and oxadiazole quinolone ( Mlala et al, 2019 ). 3-acetylursolic acid is a 3-acetylated derivative of ursolic acid, which has been reported to demonstrate similar potency and efficacy to ursolic acid when investigated for anti-proliferative and anti-migratory effects on melanoma cells ( AlQathama et al, 2020 ).…”

Anticancer activity of ursolic acid on retinoblastoma cells determined by bioinformatics analysis and validation

“…Its anti-tumor effect is particularly prominent. The anti-tumor effect of UA has been reported in a variety of diseases, including breast cancer (31), leukemia (32), prostate cancer (33), melanoma (34), endometrial cancer (35), and lung cancer (36), among others. A large number of studies have shown that UA can inhibit tumor growth and metastasis by inhibiting tumor cell proliferation, invasion, and metastasis, and its mechanism is related to the expression of related genes on tumor cells, the oxidation of fatty acids increases, and the ability to synthesize fatty acids decreases.…”