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

• Main Authors: Aljawharah AlQathama, Luying Shao, Ammar Bader, Proma Khondkar, Simon Gibbons, Jose M Prieto
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Biomolecules
• Subjects: pentacyclic triterpenes; apoptosis; melanoma; migration; cell cycle; synergism
• Online Access: https://www.mdpi.com/2218-273X/10/6/894

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-<i>O</i>-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-<i>O</i>-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.