An in vitro investigation of the apoptosis-inducing activity of corosolic acid in breast cancer cells

Document Type : Original Article

Authors

1 Medical Laboratory Techniques Department, Al-Maarif University College, Al-anbar-Ramadi, Iraq

2 Al-Anbar Health Directorate, Iraq

3 Medical Surgical Nursing Department, King Khalid University, Almahala, Abha, Saudi Arabia

4 Laboratory of Biotoxicology, Pharmacognosy and Biological Valorization of Plants (LBPVBP), Faculty of Sciences, University of Saida-Dr Moulay Tahar, 20000 Saida, Algeria

5 Department of Internal Diseases, Vice-rector for Scientific Affairs and Innovations, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan

6 Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq

7 International College, Krirk University, Bangkok, 3 Ram Inthra Rd, Khwaeng Anusawari, Khet Bang Khen, Krung Thep Maha Nakhon, 10220, Thailand

8 Medical Laboratory Technology Department, College of Medical Technology, Islamic University, Najaf, Iraq

9 Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

10 College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq

11 Medical Laboratory Science Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia

12 Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul-41001, Iraq

Abstract

Objective(s): Breast cancer is the most prevalent cancer among females with different molecular subtypes. Corosolic acid is a pentacyclic triterpenoid with anti-cancer properties. 
Materials and Methods: The MTT assay was used to assess the cytotoxic activity of corosolic acid on MDA-MB-231 and MCF7 cell lines. To determine the apoptotic cells, the flow cytometry technique was utilized. The expression levels of apoptosis-related genes and proteins were quantified using quantitative real time-PCR (qRT-PCR) and Western blotting methods. The activity of caspase enzymes was measured by spectrophotometry.  
Results: Corosolic acid significantly inhibited the proliferation of both cell lines compared with controls. This agent markedly induced apoptosis in MDA-MB-231 cells but did not affect MCF7 cells compared with controls. Treating the MADA-MB-231 and MCF7 cell lines with corosolic acid showed an inducing effect on apoptosis-associated caspases, including Caspase-8, 9, and -3, in MADA-MB-231 cells with no effect on apoptotic markers in MCF7 cells. Further experiments uncovered corosolic acid-induced apoptosis in MADA-MB-231 cells by decreasing the expression of the phosphorylated form of JAK2 and STAT3 proteins.
Conclusion: The present data suggested that corosolic acid is an apoptosis-inducing phytochemical in triple-negative breast cancer MADA-MB-231 cells. Also, corosolic acid triggered apoptosis in these cells by stimulating both pathways of apoptosis and inhibiting the JAK/STAT signaling. Furthermore, corosolic acid was found to inhibit MCF7 cell proliferation by a non-apoptotic mechanism.

Keywords


1. Wang Y, Liu ZP. Identifying biomarkers for breast cancer by gene regulatory network rewiring. BMC Bioinformatics 2022; 22:308.
2. Cuypers E, Claes BSR, Biemans R, Lieuwes NG, Glunde K, Dubois L, et al. ‘On the spot’ digital pathology of breast cancer based on single-cell mass spectrometry imaging. Anal Chem 2022; 94:6180-6190.
3. Howard FM, Olopade OI. Epidemiology of triple-negative breast cancer: A review. Cancer J 2021; 27:8-16.
4. Borri F, Granaglia A. Pathology of triple negative breast cancer. Semin Cancer Biol 2021; 72:136-145.
5. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res 2020; 22:61.
6. Dehelean CA, Marcovici I, Soica C, Mioc M, Coricovac D, Iurciuc S, et al. Plant-derived anticancer compounds as new perspectives in drug discovery and alternative therapy. Molecules 2021; 26:1109.
7. Wu TN, Chen HM, Shyur LF. Current advancements of plant-derived agents for triple-negative breast cancer therapy through deregulating cancer cell functions and reprogramming tumor microenvironment. Int J Mol Sci 2021; 22:13571.
8. Zhao J, Zhou H, An Y, Shen K, Yu L. Biological effects of corosolic acid as an anti‑inflammatory, anti‑metabolic syndrome and anti‑neoplasic natural compound (Review). Oncol Lett 2021; 21:84.
9. Şoica C, Voicu M, Ghiulai R, Dehelean C, Racoviceanu R, Trandafirescu C, et al. Natural compounds in sex hormone-dependent cancers: The role of triterpenes as therapeutic agents. Front Endocrinol (Lausanne) 2020; 11:612396.
10. Sung B, Kang YJ, Kim DH, Hwang SY, Lee Y, Kim M, et al. Corosolic acid induces apoptotic cell death in HCT116 human colon cancer cells through a caspase-dependent pathway. Int J Mol Med 2014; 33:943-949.
11. Jia M, Xiong Y, Li M, Mao Q. Corosolic acid inhibits cancer progress through inactivating YAP in hepatocellular carcinoma. Oncol Res 2020; 28:371-383.
12. Lee HS, Park JB, Lee MS, Cha EY, Kim JY, Sul JY. Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin. Mol Med Rep 2015; 12:4782-4788.
13. Pfeffer CM, Singh ATK. Apoptosis: A target for anticancer therapy. Int J Mol Sci 2018; 19:448.
14. Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY) 2016; 8:603-619.
15. Islam MS, Rahi MS, Jahangir CA, Jerin I, Hasan MM, Hoque KMF, et al. Deciphering the molecular pathways of apoptosis using purified fractions from leaf extract of Basella alba through studying the regulation of apoptosis related genes. Mol Biol Rep 2021; 48:85-96.
16. Muñoz-Pinedo C. Signaling pathways that regulate life and cell death: evolution of apoptosis in the context of self-defense. Adv Exp Med Biol 2012; 738:124-143.
17. Mengie Ayele T, Tilahun Muche Z, Behaile Teklemariam A, Bogale Kassie A, Chekol Abebe E. Role of JAK2/STAT3 signaling pathway in the tumorigenesis, chemotherapy resistance, and treatment of solid tumors: A systemic review. J Inflamm Res 2022; 15:1349-1364.
18. Rajabi S, Shojaee M, Malmir A, Rezaei Tavirani M, Noori S. Anti-breast cancer activities of 8-hydroxydaidzein by targeting breast cancer stem-like cells. J Pharm Pharm Sci 2020; 23:47-57.
19. Lyons TG. Targeted therapies for triple-negative breast cancer. Curr Treat Options Oncol 2019; 20:82.
20. Li Z, Wei H, Li S, Wu P, Mao X. The role of progesterone receptors in breast cancer. Drug Des Devel Ther 2022; 16:305-314.
21. Maniam S, Maniam S. Small molecules targeting programmed cell death in breast cancer cells. Int J Mol Sci 2021; 22:9722.
22. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol 2020; 17:395-417.
23. Yoon H, Liu RH. Effect of 2alpha-hydroxyursolic acid on NF-kappaB activation induced by TNF-alpha in human breast cancer MCF-7 cells. J Agric Food Chem 2008; 56:8412-8417.
24. Son KH, Hwang J-h, Kim D-h, Cho Y-E. Effect of corosolic acid on apoptosis and angiogenesis in MDA-MB-231 human breast cancer cells. J Nutri Health 2020; 53:111-120.
25. Jiang X, Li T, Liu RH. 2α-Hydroxyursolic acid inhibited cell proliferation and induced apoptosis in mda-mb-231 human breast cancer cells through the p38/MAPK signal transduction pathway. J Agric Food Chem 2016; 64:1806-1816.
26. Cai X, Zhang H, Tong D, Tan Z, Han D, Ji F, et al. Corosolic acid triggers mitochondria and caspase-dependent apoptotic cell death in osteosarcoma MG-63 cells. Phytother Res 2011; 25:1354-1361.
27. Nho KJ, Chun JM, Kim HK. Corosolic acid induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro. Food Chem Toxicol 2013; 56:8-17.
28. Lee MS, Cha EY, Thuong PT, Kim JY, Ahn MS, Sul JY. Down-regulation of human epidermal growth factor receptor 2/neu oncogene by corosolic acid induces cell cycle arrest and apoptosis in NCI-N87 human gastric cancer cells. Biol Pharm Bull 2010; 33:931-937.
29. Xu Y, Ge R, Du J, Xin H, Yi T, Sheng J, et al. Corosolic acid induces apoptosis through mitochondrial pathway and caspase activation in human cervix adenocarcinoma HeLa cells. Cancer Lett 2009; 284:229-237.
30. Park SK, Byun WS, Lee S, Han YT, Jeong YS, Jang K, et al. A novel small molecule STAT3 inhibitor SLSI-1216 suppresses proliferation and tumor growth of triple-negative breast cancer cells through apoptotic induction. Biochem Pharmacol 2020; 178:114053.
31. Pan L, Chen X, Fu S, Yu W, Li C, Wang T, et al. LLY17, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer. Breast Cancer Res Treat 2020; 181:31-41.
32. Dai X, Yin C, Guo G, Zhang Y, Zhao C, Qian J, et al. Schisandrin B exhibits potent anticancer activity in triple negative breast cancer by inhibiting STAT3. Toxicol Appl Pharmacol 2018; 358:110-119.
33. Fujiwara Y, Komohara Y, Ikeda T, Takeya M. Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B in tumor cells and tumor-associated macrophages. Cancer Sci 2011; 102:206-211.
34. Park KH, Joo SH, Seo JH, Kim J, Yoon G, Jeon YJ, et al. Licochalcone H induces cell cycle arrest and apoptosis in human skin cancer cells by modulating JAK2/STAT3 signaling. Biomol Ther (Seoul) 2022; 30:72-79.
35. Rajabi S, Maresca M, Yumashev AV, Choopani R, Hajimehdipoor H. The most competent plant-derived natural products for targeting apoptosis in cancer therapy. Biomolecules 2021; 11:534.