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

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School of Pharmacy, University College London, London WC1N 1AX, UK
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Department of Pharmacognosy, Pharmacy College, Umm Al-Qura University, Makkah 21955, Saudi Arabia
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School of Pharmacy, University East Anglia, Norwich NR4 7TJ, UK
4
Centre for Natural Products Discovery, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(6), 894; https://doi.org/10.3390/biom10060894
Received: 10 May 2020 / Revised: 10 June 2020 / Accepted: 10 June 2020 / Published: 11 June 2020
(This article belongs to the Section Natural and Bio-inspired Molecules)
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. View Full-Text
Keywords: pentacyclic triterpenes; apoptosis; melanoma; migration; cell cycle; synergism pentacyclic triterpenes; apoptosis; melanoma; migration; cell cycle; synergism
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AlQathama, A.; Shao, L.; Bader, A.; Khondkar, P.; Gibbons, S.; M Prieto, J. Differential Anti-Proliferative and Anti-Migratory Activities of Ursolic Acid, 3-O-Acetylursolic Acid and Their Combination Treatments with Quercetin on Melanoma Cells. Biomolecules 2020, 10, 894.

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