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

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2020 Jun 18

PMID 32545262

Citations 8

Authors

Aljawharah Alqathama

Luying Shao

Ammar Bader

Proma Khondkar

Simon Gibbons

Jose M Prieto

Affiliations

Soon will be listed here.

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--acetylursolic acid have shown similar GI 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--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.

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References

Mahmoudi M, Rabe S, Balali-Mood M, Karimi G, Tabasi N, Riahi-Zanjani B . Ursolic acid induced apoptotic cell death following activation of caspases in isolated human melanoma cells. Cell Biol Int. 2014; 39(2):230-6. DOI: 10.1002/cbin.10376. View

Chudzik M, Korzonek-Szlacheta I, Krol W . Triterpenes as potentially cytotoxic compounds. Molecules. 2015; 20(1):1610-25. PMC: 6272502. DOI: 10.3390/molecules20011610. View

Zhu H, Zhang L, Wu S, Teraishi F, Davis J, Jacob D . Induction of S-phase arrest and p21 overexpression by a small molecule 2[[3-(2,3-dichlorophenoxy)propyl] amino]ethanol in correlation with activation of ERK. Oncogene. 2004; 23(29):4984-92. DOI: 10.1038/sj.onc.1207645. View

Pradhan S, Mishra R, Sharma P, Kundu G . Quercetin and sulforaphane in combination suppress the progression of melanoma through the down-regulation of matrix metalloproteinase-9. Exp Ther Med. 2012; 1(6):915-920. PMC: 3446732. DOI: 10.3892/etm.2010.144. View

Wang X, Li L, Wang B, Xiang J . Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cells. J Huazhong Univ Sci Technolog Med Sci. 2009; 29(6):761-4. DOI: 10.1007/s11596-009-0618-y. View

Li Y, Gan G, Zhang H, Wu H, Li C, Huang Y . A flavonoid glycoside isolated from Smilax china L. rhizome in vitro anticancer effects on human cancer cell lines. J Ethnopharmacol. 2007; 113(1):115-24. DOI: 10.1016/j.jep.2007.05.016. View

Vichai V, Kirtikara K . Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2007; 1(3):1112-6. DOI: 10.1038/nprot.2006.179. View

Biswas R, Mandal S, Dutta S, Bhattacharyya S, Boujedaini N, Khuda-Bukhsh A . Thujone-Rich Fraction of Thuja occidentalis Demonstrates Major Anti-Cancer Potentials: Evidences from In Vitro Studies on A375 Cells. Evid Based Complement Alternat Med. 2011; 2011:568148. PMC: 3106972. DOI: 10.1093/ecam/neq042. View

Wang X, Zhang F, Yang L, Mei Y, Long H, Zhang X . Ursolic acid inhibits proliferation and induces apoptosis of cancer cells in vitro and in vivo. J Biomed Biotechnol. 2011; 2011:419343. PMC: 3116524. DOI: 10.1155/2011/419343. View

10.

Lee Y, Wang E, Kumar N, Glickman R . Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV-VIS broadband radiation. Apoptosis. 2013; 19(5):816-28. DOI: 10.1007/s10495-013-0962-z. View

11.

Ali A, Zaki M, Parveen A, Ali Z, Khan I . Bioassay guided isolation of mosquito biting deterrent compounds from Strumpfia maritima. Pest Manag Sci. 2020; 76(7):2342-2346. DOI: 10.1002/ps.5769. View

12.

Kassi E, Sourlingas T, Spiliotaki M, Papoutsi Z, Pratsinis H, Aligiannis N . Ursolic acid triggers apoptosis and Bcl-2 downregulation in MCF-7 breast cancer cells. Cancer Invest. 2009; 27(7):723-33. DOI: 10.1080/07357900802672712. View

13.

Wozniak L, Skapska S, Marszalek K . Ursolic Acid--A Pentacyclic Triterpenoid with a Wide Spectrum of Pharmacological Activities. Molecules. 2015; 20(11):20614-41. PMC: 6332387. DOI: 10.3390/molecules201119721. View

14.

Wang H, Ke M, Tian Y, Wang J, Li B, Wang Y . BF-30 selectively inhibits melanoma cell proliferation via cytoplasmic membrane permeabilization and DNA-binding in vitro and in B16F10-bearing mice. Eur J Pharmacol. 2013; 707(1-3):1-10. DOI: 10.1016/j.ejphar.2013.03.028. View

15.

Shan J, Xuan Y, Zheng S, Dong Q, Zhang S . Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J Zhejiang Univ Sci B. 2009; 10(9):668-74. PMC: 2738836. DOI: 10.1631/jzus.B0920149. View

16.

Mazumder K, Tanaka K, Fukase K . Cytotoxic activity of ursolic acid derivatives obtained by isolation and oxidative derivatization. Molecules. 2013; 18(8):8929-44. PMC: 6269999. DOI: 10.3390/molecules18088929. View

17.

Shao J, Dai Y, Xue J, Wang J, Lin F, Guo Y . In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives. Eur J Med Chem. 2011; 46(7):2652-61. DOI: 10.1016/j.ejmech.2011.03.050. View

18.

Ciftci H, Radwan M, E Ozturk S, Ulusoy N, Sozer E, Ellakwa D . Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity. Molecules. 2019; 24(19). PMC: 6804044. DOI: 10.3390/molecules24193535. View

19.

Duval R, Harmand P, Jayat-Vignoles C, Cook-Moreau J, Pinon A, Delage C . Differential involvement of mitochondria during ursolic acid-induced apoptotic process in HaCaT and M4Beu cells. Oncol Rep. 2007; 19(1):145-9. View

20.

Harmand P, Duval R, Delage C, Simon A . Ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in M4Beu melanoma cells. Int J Cancer. 2004; 114(1):1-11. DOI: 10.1002/ijc.20588. View