Effect of Ellagic Acid and Cryptotanshinone on Cell Viability/Cytotoxicity, Metastasis, and Oxidative Stress in Triple-Negative Breast Cancer Cells

Yıl 2024, Cilt: 14 Sayı: 1, 46 - 53, 24.04.2024

Ümit Yılmaz , Mehmet Fatih Seyhan

https://doi.org/10.26650/experimed.1430845

Öz

Objective: Triple-negative breast cancer (TNBC) has the highest rate of metastases and relapses as well as the worst overall survival of all breast cancers. Here, we aimed to investigate the effects of ellagic acid and cryptotanshinone, which are known to have antioxidant, antimutagenic, anticancer, and apoptotic effects, on cell viability/cytotoxicity, metastasis, and oxidative stress in MDA-MB-231 cells.

Materials and Methods: The effects of various concentrations of ellagic acid and cryptotanshinone on cell viability or cytotoxicity in TNBC cells were determined by WST-1. A scratch assay was performed to determine the effects of ellagic acid and cryptotanshinone on cell migration and metastasis, and a DCF-DA test was performed to determine the reactive oxygen species (ROS) levels.

Results: MDA-MB-231 cells exposed to cryptotanshinone exhibited reduced cell proliferation by approximately 50%, particularly at 20 μg/mL after 48 h. The cell viability decreased by 75% at 20 μg/mL after 72 h of cryptotanshinone exposure. After 48 h of exposure to ellagic acid at 40 μg/mL, the scratch in the MDA-MB-231 cells closed. In addition, treatment with cryptotanshinone at 25 μg/mL covered the scratch after 72 h. Ellagic acid (40 μg/mL) induced oxidative stress at 24 h, and cryptotanshinone (25 μg/mL) at 48 and 72 h. Furthermore, the fluorescence intensity of MDA-MB-231 cells was increased by exposure to ellagic acid (40 μg/mL) and cryptotanshinone (25 μg/mL) after 24 h compared to the negative control.

Conclusion: Ellagic acid and cryptotanshinone may inhibit cell proliferation, suppress cell migration, and induce the accumulation of intracellular ROS in MDA-MB-231 cells.

Anahtar Kelimeler

Triple-negative breast cancer, MDA-MB-231, cell culture, ellagic acid, cryptotanshinone

Etik Beyan

Bu çalışma bir hücre kültürü çalışmasıdır ve bu nedenle etik kurul onayına ihtiyaç yoktur.

Destekleyen Kurum

Karabük Üniversitesi

Proje Numarası

The present work was supported by the Research Fund of Karabuk University [Project No: 22-DS-118].

Kaynakça

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49. google scholar
• Lee A, Djamgoz MBA. Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev 2018; 62: 110-22. google scholar
• Diaz P, Jeong SC, Lee S, Khoo C, Koyyalamudi SR. Antioxidant and anti-inflammatory activities of selected medicinal plants and fungi containing phenolic and flavonoid compounds. Chin Med 2012; 7(1): 26. google scholar
• Chikara S, Nagaprashantha LD, Singhal J, Horne D, Awasthi S, Singhal SS. Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment. Cancer Lett 2018; 413: 122-34. google scholar
• Vekiari SA, Gordon MH, Garcia-Macias P, Labrinea H. Extraction and determination of ellagic acid contentin chestnut bark and fruit. Food Chem 2008; 110(4): 1007-11. google scholar
• Ramadan DT, Ali MAM, Yahya SM, El-Sayed WM. Correlation between antioxidant/antimutagenic and antiproliferative activity of some phytochemicals. Anticancer Agents Med Chem 2019; 19(12): 1481-90. google scholar
• Kaur H, Ghosh S, Kumar P, Basu B, Nagpal K. Ellagic acid-loaded, tween 80-coated, chitosan nanoparticles as a promising therapeutic approach against breast cancer: In-vitro and in-vivo study. Life Sci 2021; 284: 119927. google scholar
• Ceci C, Lacal PM, Tentori L, De Martino MG, Miano R, Graziani G. Experimental evidence of the antitumor, antimetastatic and antiangiogenic activity of ellagic acid. Nutrients 2018; 10(11) : 1756. google scholar
• Cheshomi H, Bahrami AR, Matin MM. Ellagic acid and human cancers: a systems pharmacology and docking study to identify principal hub genes and main mechanisms of action. Mol Divers 2021; 25(1): 333-49. google scholar
• Golmohammadi M, Zamanian MY, Jalal SM, Noraldeen SAM, Ramirez-Coronel AA, Oudaha KH, et al. A comprehensive review on ellagic acid in breast cancer treatment: from cellular effects to molecular mechanisms of action. Food Sci Nutr 2023; 11(12): 7458-68. google scholar
• Yu XY, Lin SG, Chen X, Zhou ZW, Liang J, Duan W, et al. Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimer’s disease, across the blood-brain barrier. Curr Drug Metab 2007; 8(4): 365-78. google scholar
• Chen W, Lu Y, Chen G, Huang S. Molecular evidence of cryptotanshinone for treatment and prevention of human cancer. Anticancer Agents Med Chem 2013; 13(7): 979-87. google scholar
• Chen Q, Zhuang Q, Mao W, Xu XM, Wang LH, Wang HB. Inhibitory effect of cryptotanshinone on angiogenesis and Wnt/beta-catenin signaling pathway in human umbilical vein endothelial cells. Chin J Integr Med 2014; 20(10): 743-50. google scholar
• Tang S, Shen XY, Huang HQ, Xu SW, Yu Y, Zhou CH, et al. Cryptotanshinone suppressed inflammatory cytokines secretion in RAW264.7 macrophages through inhibition of the NF-kappaB and MAPK signaling pathways. Inflammation 2011; 34(2): 111-8. google scholar
• Kim SA, Kang OH, Kwon DY. Cryptotanshinone induces cell cycle arrest and apoptosis of NSCLC cells through the PI3K/Akt/GSK-3beta pathway. Int J Mol Sci 2018; 19(9): 2739. google scholar
• Chen Z, Zhu R, Zheng J, Chen C, Huang C, Ma J, et al. Cryptotanshinone inhibits proliferation yet induces apoptosis by suppressing STAT3 signals in renal cell carcinoma. Oncotarget 2017; 8(30): 50023-33. google scholar
• Dalil D, Iranzadeh S, Kohansal S. Anticancer potential of cryptotanshinone on breast cancer treatment; a narrative review. Front Pharmacol 2022; 13: 979634. google scholar
• Shi D, Li H, Zhang Z, He Y, Chen M, Sun L, et al. Cryptotanshinone inhibits proliferation and induces apoptosis of breast cancer MCF-7 cells via GPER mediated PI3K/AKT signaling pathway. PLoS One 2022; 17(1): e0262389. google scholar
• Jiang L, Wang Y, Liu G, Liu H, Zhu F, Ji H, et al. C-Phycocyanin exerts anti-cancer effects via the MAPK signaling pathway in MDA-MB-231 cells. Cancer Cell Int 2018; 18: 12. google scholar
• Xia M, Yu H, Gu S, Xu Y, Su J, Li H, et al. p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system. Int J Oncol 2014; 45(6): 2341-8. google scholar
• Han DH, Lee MJ, Kim JH. Antioxidant and apoptosis-inducing activities of ellagic acid. Anticancer Res 2006; 26(5A): 3601-6. google scholar
• Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B, et al. Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound. Carcinogenesis 2005; 26(4): 821-6. google scholar
• Shi L, Gao X, Li X, Jiang N, Luo F, Gu C, et al. Ellagic acid enhances the efficacy of PI3K inhibitor GDC-0941 in breast cancer cells. Curr Mol Med 2015; 15(5): 478-86. google scholar
• Wang N, Wang ZY, Mo SL, Loo TY, Wang DM, Luo HB, et al. Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer. Breast Cancer Res Treat 2012; 134(3): 943-55. google scholar
• Ahire V, Kumar A, Mishra KP, Kulkarni G. Ellagic acid enhances apoptotic sensitivity of breast cancer cells to gamma-radiation. Nutr Cancer 2017; 69(6): 904-10. google scholar
• Zhang T, Chen HS, Wang LF, Bai MH, Wang YC, Jiang XF, et al. Ellagic acid exerts anti-proliferation effects via modulation of Tgf-beta/ Smad3 signaling in MCF-7 breast cancer cells. Asian Pac J Cancer Prev 2014; 15(1): 273-6. google scholar
• Chen HS, Bai MH, Zhang T, Li GD, Liu M. Ellagic acid induces cell cycle arrest and apoptosis through TGF-beta/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol 2015; 46(4): 1730-8. google scholar
• Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, et al. Ellagic acid controls cell proliferation and induces apoptosis in breast cancer cells via inhibition of cyclin-dependent kinase 6. Int J Mol Sci 2020; 21(10): 3526. google scholar
• Wu YH, Wu YR, Li B, Yan ZY. Cryptotanshinone: a review of its pharmacology activities and molecular mechanisms. Fitoterapia 2020; 145: 104633. google scholar
• Noori S, Nourbakhsh M, Imani H, Deravi N, Salehi N, Abdolvahabi Z. Naringenin and cryptotanshinone shift the immune response towards Th1 and modulate T regulatory cells via JAK2/STAT3 pathway in breast cancer. BMC Complement Med Ther 2022; 22(1): 145. google scholar
• Zhou J, Xu XZ, Hu YR, Hu AR, Zhu CL, Gao GS. Cryptotanshinone induces inhibition of breast tumor growth by cytotoxic CD4+ T cells through the JAK2/STAT4/ perforin pathway. Asian Pac J Cancer Prev 2014; 15(6): 2439-45. google scholar
• Zhang YF, Zhang M, Huang XL, Fu YJ, Jiang YH, Bao LL, et al. The combination of arsenic and cryptotanshinone induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in breast cancer cells. Metallomics 2015; 7(1): 16573. google scholar
• Park IJ, Kim MJ, Park OJ, Choe W, Kang I, Kim SS, et al. Cryptotanshinone induces ER stress-mediated apoptosis in HepG2 and MCF7 cells. Apoptosis 2012; 17(3): 248-57. google scholar
• Pan Y, Shi J, Ni W, Liu Y, Wang S, Wang X, et al. Cryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer. J Cell Mol Med 2017; 21(9): 2129-39. google scholar
• Li S, Wang H, Hong L, Liu W, Huang F, Wang J, et al. Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling. Cancer Biol Ther 2015; 16(1): 176-84. google scholar
• Li H, Gao C, Liang Q, Liu C, Liu L, Zhuang J, et al. Cryptotanshinone is a intervention for ER-positive breast cancer: an integrated approach to the study of natural product intervention mechanisms. Front Pharmacol 2020; 11: 592109. google scholar
• Zhou J, Su CM, Chen HA, Du S, Li CW, Wu H, et al. Cryptanshinone inhibits the glycolysis and inhibits cell migration through PKM2/ beta-catenin axis in breast cancer. Onco Targets Ther 2020; 13: 8629-39. google scholar
• Shi D, Zhao P, Cui L, Li H, Sun L, Niu J, et al. Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells. BMC Pharmacol Toxicol 2020; 21(1): 32. google scholar
• Gong Y, Li Y, Abdolmaleky HM, Li L, Zhou JR. Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function. PLoS One 2012; 7(4): e33656. google scholar
• Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, et al. Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules. 2019; 9(11) ):735. google scholar