Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells

Ege Arzuk; Ali Ergüç; Serhat Demir; Nehir Ünver Somer; İclal Tan; Ecrin Atış

Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells

Abstract

Hepatocellular carcinoma is one of the most severe and life-threatening types of cancer. The conventional treatment of hepatoma has significant challenges due to the adverse effects of chemotherapy, leading to treatment failure and decreased survival. Therefore, developing and investigating novel and safer anticancer drugs and establishing more effective therapeutic regimens is a crucial field of research. The Haplophyllum megalanthum-derived compound matairesinol has demonstrated antiproliferative and antitumor activity against various types of cancer, including pancreatic, breast, and prostate cancer. However, the potential effects of matairesinol on liver cancer, as well as the underlying molecular mechanisms associated with its anticancer activity, have yet to be thoroughly elucidated. In the current study, we demonstrated that matairesinol inhibited the viability of human hepatoma cells in a dose-dependent manner. Besides, at IC50 and higher doses, matairesinol induced oxidative stress and impaired mitochondrial membrane potential and ATP levels, two evidence of mitochondrial damage. Moreover, matairesinol exposure led to significant caspase-3 activation, a hallmark of apoptosis. These results indicate that mitochondrial damage and caspase-3 activation may contribute to the cytotoxic effect of matairesinol on liver cancer cells.

Keywords

References

[1] Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res. 2021;40(1):172. https://doi.org/10.1186/s13046-021-01968-w
[2] Wang J, Jiang YF. Natural compounds as anticancer agents: Experimental evidence. World J Exp Med. 2012;2(3):45 57. https://doi.org/10.5493/wjem.v2.i3.45
[3] Lin SR, Chang CH, Hsu CF, Torvaldson E, Holmbom T, Eklund P, Unkila M, Sjöholm R, Eriksson JE. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br J Pharmacol. 2020;177(6):1409-1423. https://doi.org/10.1111/bph.14816
[4] Sung YY, Lee AY, Kim HK. Forsythia suspensa fruit extracts and the constituent matairesinol confer anti-allergic effects in an allergic dermatitis mouse model. J Ethnopharmacol. 2016;187:49-56. https://doi.org/10.1016/j.jep.2016.04.015
[5] Chang H, Wang Y, Gao X, Song Z, Awale S, Han N, Liu Z, Yin J. Lignans from the root of Wikstroemia indica and their cytotoxic activity against PANC-1 human pancreatic cancer cells. Fitoterapia. 2017;121: 31–37. https://doi.org/10.1016/j.fitote.2017.06.012
[6] Mahajan M, Suryavanshi S, Bhowmick S, Alasmary FA, Almutairi TM, Islam MA, Kaul-Ghanekar R. Matairesinol, an active constituent of HC9 polyherbal formulation, exhibits HDAC8 inhibitory and anticancer activity. Biophys Chem. 2021;273:106588. https://doi.org/10.1016/j.bpc.2021.106588
[7] Peuhu E, Rivero-Müller A, Stykki H, Torvaldson E, Holmbom T, Eklund P, Unkila M, Sjöholm R, Eriksson JE. Inhibition of Akt signaling by the lignan matairesinol sensitizes prostate cancer cells to TRAIL-induced apoptosis. Oncogene. 2010;29(6):898-908. https://doi.org/10.1038/onc.2009.386
[8] Wang C, Youle RJ. The role of mitochondria in apoptosis. Annu Rev Genet. 2009;43:95-118. https://doi.org/10.1146/annurev-genet-102108-134850

[9] Luo Y, Ma J, Lu W. The Significance of Mitochondrial Dysfunction in Cancer. Int J Mol Sci. 2020;21(16):5598. https://doi.org/10.3390/ijms21165598
[10] Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8(21):2003-2014. https://doi.org/10.3969/j.issn.1673-5374.2013.21.009
[11] Ma J, Pan Z, Du H, et al. Luteolin induces apoptosis by impairing mitochondrial function and targeting the intrinsic apoptosis pathway in gastric cancer cells. Oncol Lett. 2023;26(2):327. https://doi.org/10.3892/ol.2023.13913
[12] Yang Y, He PY, Zhang Y, Li N. Natural products targeting the mitochondria in cancers. Molecules. 2020;26(1):92. https://doi.org/10.3390/molecules26010092
[13] Won YS, Kim JH, Lizardo RCM, Min HJ, Cho HD, Hong SM, Seo KI. The flavonol isoquercitrin promotes mitochondrial-dependent apoptosis in SK-Mel-2 melanoma cell via the PI3K/AKT/mTOR pathway. Nutrients. 2020;12(12):3683. https://doi.org/10.3390/nu12123683
[14] Diogo CV, Machado NG, Barbosa IA, Serafim TL, Burgeiro A, Oliveira PJ. Berberine as a promising safe anti-cancer agent - is there a role for https://doi.org/10.2174/138945011795528930
[15] Lee W, Song G, Bae H. Matairesinol induces mitochondrial dysfunction and exerts synergistic anticancer effects with 5-fluorouracil in pancreatic cancer cells. Mar Drugs. 2022;20(8):473. https://doi.org/10.3390/md20080473
[16] Mittler R. ROS Are Good. Trends Plant Sci. 2017;22(1):11-19. https://doi.org/10.1016/j.tplants.2016.08.002
[17] Hampton MB, Orrenius S. Redox regulation of apoptotic cell death in the immune system. Toxicol Lett. 1998;102 103:355-358. https://doi.org/10.1016/s0378-4274(98)00333-6.
[18] Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. https://doi.org/10.1080/01926230701320337
[19] Eskandari E, Eaves CJ. Paradoxical roles of caspase-3 in regulating cell survival, proliferation, and tumorigenesis. J Cell Biol. 2022;221(6):e202201159. https://doi.org/10.1083/jcb.202201159
[20] Demir S. PhD Thesis. Pharmacognostical studies on Haplophyllum megalanthum Bornm. plant. Department of Pharmacology, Faculty of Pharmacy, Ege University, İzmir, Turkey, 2022.
[21] Petersen MJ, Liang C, Kjaerulff L, Ndi C, Semple S, Buirchell B, Coriani S, Møller BL, Staerk D. Serrulatane diterpenoids from the leaves of Eremophila glabra and their potential as antihyperglycemic drug leads. Phytochemistry. 2022;196:113072. https://doi.org/10.1016/j.phytochem.2021.113072
[22] Tan XW, Xia H, Xu JH, Cao JG. Induction of apoptosis in human liver carcinoma HepG2 cell line by 5-allyl-7-gen difluoromethylenechrysin. World J Gastroenterol. 2009;15(18):2234-2239. https://doi.org10.3748/wjg.15.2234
[23] Reiniers MJ, de Haan LR, Reeskamp LF, Broekgaarden M, van Golen RF, Heger M. Analysis and optimization of conditions for the use of 2',7'-dichlorofluorescein diacetate in cultured hepatocytes. Antioxidants . 2021;10(5):674. https://doi.org/10.3390/antiox10050674
[24] Ghosh R, Goswami SK, Feitoza LFBB, Hammock B, Gomes AV. Diclofenac induces proteasome and mitochondrial dysfunction in murine cardiomyocytes and hearts. Int J Cardiol. 2016;223:923-935. https://doi:10.1016/j.ijcard.2016.08.233
[25] Zhang J, Ren L, Yang X, White M, Greenhaw J, Harris T, Wu Q, Bryant M, Papoian T, Mattes W, Shi Q. Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018;291:138-148. https://doi.org/10.1016/j.toxlet.2018.04.010
[26] Bashir R, Ahmad Zargar O, Hamid Dar A, Yedukondalu N, Parvaiz Q, Hamid R. The modulation of PI3K/Akt pathway by 3β hydroxylup-12-en-28-oic acid isolated from Thymus linearis induces cell death in HCT-116 cells. Chem Biol Drug Des. 2022;99(1):162-178. https://doi.org/10.1111/cbdd.13957

Details

Primary Language

English

Subjects

Pharmaceutical Toxicology

Journal Section

Research Article

Authors

Ege Arzuk ^* This is me
0000-0002-3239-4855
Türkiye

Ali Ergüç
0000-0002-9791-4399
Türkiye

Serhat Demir This is me
0000-0002-1228-8932
Türkiye

Nehir Ünver Somer
0000-0001-8939-1762
Türkiye

İclal Tan
0009-0001-2006-5480
Türkiye

Ecrin Atış
0009-0001-8475-8067
Türkiye

Publication Date

June 28, 2025

Submission Date

December 10, 2023

Acceptance Date

February 29, 2024

Published in Issue

Year 2024 Volume: 28 Number: 6

IZ

https://izlik.org/JA75PW54EM

Cite

RIS / Bibtex

APA

Arzuk, E., Ergüç, A., Demir, S., Ünver Somer, N., Tan, İ., & Atış, E. (2025). Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells. Journal of Research in Pharmacy, 28(6), 2001-2007. https://izlik.org/JA75PW54EM

AMA

1.Arzuk E, Ergüç A, Demir S, Ünver Somer N, Tan İ, Atış E. Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells. J. Res. Pharm. 2025;28(6):2001-2007. https://izlik.org/JA75PW54EM

Chicago

Arzuk, Ege, Ali Ergüç, Serhat Demir, Nehir Ünver Somer, İclal Tan, and Ecrin Atış. 2025. “Matairesinol Induced Antiproliferative Effects via Mitochondrial Dysfunction in HepG2 Cells”. Journal of Research in Pharmacy 28 (6): 2001-7. https://izlik.org/JA75PW54EM.

EndNote

Arzuk E, Ergüç A, Demir S, Ünver Somer N, Tan İ, Atış E (July 1, 2025) Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells. Journal of Research in Pharmacy 28 6 2001–2007.

IEEE

[1]E. Arzuk, A. Ergüç, S. Demir, N. Ünver Somer, İ. Tan, and E. Atış, “Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells”, J. Res. Pharm., vol. 28, no. 6, pp. 2001–2007, July 2025, [Online]. Available: https://izlik.org/JA75PW54EM

ISNAD

Arzuk, Ege - Ergüç, Ali - Demir, Serhat - Ünver Somer, Nehir - Tan, İclal - Atış, Ecrin. “Matairesinol Induced Antiproliferative Effects via Mitochondrial Dysfunction in HepG2 Cells”. Journal of Research in Pharmacy 28/6 (July 1, 2025): 2001-2007. https://izlik.org/JA75PW54EM.

JAMA

1.Arzuk E, Ergüç A, Demir S, Ünver Somer N, Tan İ, Atış E. Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells. J. Res. Pharm. 2025;28:2001–2007.

MLA

Arzuk, Ege, et al. “Matairesinol Induced Antiproliferative Effects via Mitochondrial Dysfunction in HepG2 Cells”. Journal of Research in Pharmacy, vol. 28, no. 6, July 2025, pp. 2001-7, https://izlik.org/JA75PW54EM.

Vancouver

1.Ege Arzuk, Ali Ergüç, Serhat Demir, Nehir Ünver Somer, İclal Tan, Ecrin Atış. Matairesinol induced antiproliferative effects via mitochondrial dysfunction in HepG2 cells. J. Res. Pharm. [Internet]. 2025 Jul. 1;28(6):2001-7. Available from: https://izlik.org/JA75PW54EM