Therapeutic Potential of Flavonoids in Modulating Mitochondrial Activity in Liver Cancer: Insights from HepG2 Cell Studies

Ghazal Abdullahi Olawale ¹, Nozlena Abdul Samad ¹*, Muath H. S. Helal ²

This review highlights the potential of flavonoids as therapeutic agents in liver cancer, focusing on HepG2 cell models.

Abstract

Background: Cancer, a leading cause of mortality globally, affects various organs, including the liver, with liver cancer contributing to approximately 830,000 deaths in 2020. In Malaysia, liver cancer is increasingly prevalent. The HepG2 cell line, derived from human hepatoma, is widely used for studying liver cancer and drug-induced liver injuries. Flavonoids, a group of polyphenolic compounds found in plants, have gained attention for their diverse pharmacological activities, including their potential to mitigate carcinogenesis and tumorigenesis in liver cancers. Methods: This review synthesizes findings from studies investigating the impact of flavonoids on liver cancer, focusing on the HepG2 cell line. We explore flavonoid subtypes and their therapeutic roles, including their antioxidant, anti-inflammatory, anti-angiogenic, and cytotoxic properties. Research on mitochondrial function in cancer cells and how flavonoids influence mitochondrial activity in the HepG2 cell line is also assessed. Results: Flavonoids demonstrated significant antioxidant properties by modulating reactive oxygen species (ROS) levels and maintaining mitochondrial homeostasis in HepG2 cells. Key flavonoids, including quercetin, naringenin, and kaempferol, exhibited strong anti-inflammatory and anti-angiogenic effects. Furthermore, cytotoxic flavonoids induced apoptosis in HepG2 cells through mitochondrial disruption and ROS generation, with certain compounds showing selective toxicity to cancer cells. Conclusion: Flavonoids exhibit promising therapeutic potential in liver cancer by targeting oxidative stress, inflammation, and angiogenesis while promoting apoptosis in HepG2 cells. Their ability to modulate mitochondrial function positions them as potent agents for further investigation in liver cancer therapy.

Keywords: Flavonoids, HepG2 cells, Mitochondria, Liver cancer, Antioxidants, Apoptosis, ROS

References

Abdal Dayem, A., Hossain, M., Lee, S., Kim, K., Saha, S., Yang, G. M., et al. (2017). The role of reactive oxygen species (ROS) in the biological activities of metallic nanoparticles. International Journal of Molecular Sciences, 18(1), 120.

Al-Dabbagh, B., Elhaty, I. A., Elhaw, M., Murali, C., Al Mansoori, A., Awad, B., et al. (2019). Antioxidant and anticancer activities of chamomile (Matricaria recutita L.). BMC Research Notes, 12(1), 3. https://doi.org/10.1186/s13104-018-3960-y

Arzumanian, V. A., Kiseleva, O. I., & Poverennaya, E. V. (2021). The curious case of the HepG2 cell line: 40 years of expertise. International Journal of Molecular Sciences, 22. MDPI.

Asnaashari, S., Amjad, E., & Sokouti, B. (2023). Synergistic effects of flavonoids and paclitaxel in cancer treatment: A systematic review. Cancer Cell International, 23(1), 211. https://doi.org/10.1186/s12935-023-03052-z

Ballard, C. R., & Maróstica, M. R. (2019). Health benefits of flavonoids. In Bioactive compounds: Health benefits and potential applications (pp. 185–201). Elsevier.

Barba, I., Carrillo-Bosch, L., & Seoane, J. (2024). Targeting the Warburg effect in cancer: Where do we stand? International Journal of Molecular Sciences, 25(6), 3142.

Chand, P., Kumar, H., Jain, R., Jain, A., & Jain, V. (2023). Flavonoids as omnipotent candidates for cancer management. South African Journal of Botany, 158, 334–346.

Darband, S. G., Kaviani, M., Yousefi, B., Sadighparvar, S., Pakdel, F. G., Attari, J. A., et al. (2018). Quercetin: A functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. Journal of Cellular Physiology, 233(9), 6544–6560.

Devi, K. P., Rajavel, T., Habtemariam, S., Nabavi, S. F., & Nabavi, S. M. (2015). Molecular mechanisms underlying anticancer effects of myricetin. Life Sciences, 142, 19–25. https://www.sciencedirect.com/science/article/pii/S0024320515300308

Farzaei, M. H., Singh, A. K., Kumar, R., Croley, C. R., Pandey, A. K., Coy-Barrera, E., et al. (2019). Targeting inflammation by flavonoids: Novel therapeutic strategy for metabolic disorders. International Journal of Molecular Sciences, 20(19). https://www.mdpi.com/1422-0067/20/19/4957

Feng, C. P., Tang, H. M., Huang, S., Hou, S. Z., Liang, J., & Huang, W. (2016). Evaluation of the effects of the water-soluble total flavonoids from Isodon lophanthoides var. gerardianus (Benth.) H. Hara on apoptosis in HepG2 cells: Investigation of the most relevant mechanisms. Journal of Ethnopharmacology, 188, 70–79.

Ferraz, C. R., Carvalho, T. T., Manchope, M. F., Artero, N. A., Rasquel-Oliveira, F. S., Fattori, V., et al. (2020). Therapeutic potential of flavonoids in pain and inflammation: Mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules, 25(3). https://www.mdpi.com/1420-3049/25/3/762

Galatro, A., Lucini Mas, A., Luquet, M., Fraga, C. G., & Galleano, M. (2024). Plants as a source of dietary bioactives: Flavonoids and basis for their health benefits. Aspects of Molecular Medicine, 4, 100048.

Genovese, I., Carinci, M., Modesti, L., Aguiari, G., Pinton, P., & Giorgi, C. (2021). Mitochondria: Insights into crucial features to overcome cancer chemoresistance. International Journal of Molecular Sciences, 22(12), 6422.

Gerschman, R., Gilbert, D. L., Nye, S. W., Dwyer, P., & Fenn, W. O. (1954). Oxygen poisoning and X-irradiation: A mechanism in common. Science, 119(3097), 623–626. https://doi.org/10.1126/science.119.3097.623

Goldring, C. E., Guillouzo, A., Hewitt, P. G., Ingelman-Sundberg, M., Jensen, K. G., Juhila, S., et al. (2020). Managing the challenge of drug-induced liver injury: A roadmap for the development and deployment of preclinical predictive models. Nature Reviews Drug Discovery, 19(2). https://univ-rennes.hal.science/hal-02397617

González, R., Ballester, I., López-Posadas, R., Suárez, M. D., Zarzuelo, A., Martínez-Augustin, O., et al. (2011). Effects of flavonoids and other polyphenols on inflammation. Critical Reviews in Food Science and Nutrition, 51(4), 331–362.

Gupta, A., Jain, P., Nagori, K., Adnan, M., & Ajazuddin. (2024). Treatment strategies for psoriasis using flavonoids from traditional Chinese medicine. Pharmacological Research - Modern Chinese Medicine, 12, 100463.

Huang, Q., Zhan, L., Cao, H., Li, J., Lyu, Y., Guo, X., et al. (2016). Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy, 12(6), 999–1014.

Huang, R., Zhang, X., Gracia-Sancho, J., & Xie, W. (2022). Liver regeneration: Cellular origin and molecular mechanisms. Liver International, 42(7), 1486–1495.

Jung, H. A., Abdul, Q. A., Byun, J. S., Joung, E. J., Gwon, W. G., & Lee, M. S., et al. (2017). Protective effects of flavonoids isolated from Korean milk thistle Cirsium japonicum var. maackii (Maxim.) Matsum on tert-butyl hydroperoxide-induced hepatotoxicity in HepG2 cells. Journal of Ethnopharmacology, 209, 62–72.

Kamble, S. S., & Gacche, R. N. (2019). Evaluation of anti-breast cancer, anti-angiogenic and antioxidant properties of selected medicinal plants. European Journal of Integrative Medicine, 25, 13–19. https://www.sciencedirect.com/science/article/pii/S1876382018306590

Klein, K., He, K., Younes, A. I., Barsoumian, H. B., Chen, D., Ozgen, T., et al. (2020). Role of mitochondria in cancer immune evasion and potential therapeutic approaches. Frontiers in Immunology, 11, 129–139.

Kuete, V., Mbaveng, A. T., Zeino, M., Fozing, C. D., Ngameni, B., Kapche, G. D. W. F., et al. (2015). Cytotoxicity of three naturally occurring flavonoid-derived compounds (artocarpesin, cycloartocarpesin, and isobavachalcone) towards multi-factorial drug-resistant cancer cells. Phytomedicine, 22(12), 1096–1102.

Kuete, V., Nkuete, A. H. L., Mbaveng, A. T., Wiench, B., Wabo, H. K., Tane, P., et al. (2014). Cytotoxicity and modes of action of 4′-hydroxy-2′,6′-dimethoxychalcone and other flavonoids toward drug-sensitive and multidrug-resistant cancer cell lines. Phytomedicine, 21(12), 1651–1657.

Li, H., Zhang, X., & Wang, W. (2017). Anticancer activity of 5, 7-dimethoxyflavone against liver cancer cell line HepG2 involves apoptosis, ROS generation and cell cycle arrest. African Journal of Traditional, Complementary and Alternative Medicines, 14(4), 213–220.

Li, L., Qin, Y., Xin, X., Wang, S., Liu, Z., & Feng, X. (2023). The great potential of flavonoids as candidate drugs for NAFLD. Biomedicine & Pharmacotherapy, 164. Elsevier Masson s.r.l.

Li, M., Wang, L., Wang, Y., Zhang, S., Zhou, G., Lieshout, R., et al. (2020). Mitochondrial fusion via OPA1 and MFN1 supports liver tumor cell metabolism and growth. Cells, 9(1), 121.

Li, Y., Duan, S., Jia, H., Bai, C., Zhang, L., & Wang, Z. (2014). Flavonoids from tartary buckwheat induce G2/M cell cycle arrest and apoptosis in human hepatoma HepG2 cells. Acta Biochimica et Biophysica Sinica (Shanghai), 46(6), 460–470.

Liu, C., Jin, Y., & Fan, Z. (2021). The mechanism of Warburg effect-induced chemoresistance in cancer. Frontiers in Oncology, 11. https://doi.org/10.3389/fonc.2021.679682

Liu, Y., & Shi, Y. (2020). Mitochondria as a target in cancer treatment. MedComm, 1, 129–139.

Liu, Y., Luo, J., Peng, L., Zhang, Q., Rong, X., Luo, Y., et al. (2024). Flavonoids: Potential therapeutic agents for cardiovascular disease. Heliyon, 10(12), e32563.

Liu, Y., Sun, Y., Guo, Y., Shi, X., Chen, X., Feng, W., et al. (2023). An overview: The diversified role of mitochondria in cancer metabolism. International Journal of Biological Sciences, 19(4), 897–915.

López-Terrada, D., Cheung, S. W., Finegold, M. J., & Knowles, B. B. (2009). Hep G2 is a hepatoblastoma-derived cell line. Human Pathology, 40(10), 1512–1515.

Ma, Y., Wang, L., & Jia, R. (2020). The role of mitochondrial dynamics in human cancers. American Journal of Cancer Research, 10(6), 1328–1347.

Missiroli, S., Perrone, M., Genovese, I., Pinton, P., & Giorgi, C. (2020). Cancer metabolism and mitochondria: Finding novel mechanisms to fight tumours. EBioMedicine, 59. https://doi.org/10.1016/j.ebiom.2020.102940

Mohamed, R., Raihan, R., Azzeri, A., & Shabaruddin, F. H. (2018). Hepatocellular carcinoma in Malaysia and its changing trend. Euroasian Journal of Hepato-Gastroenterology, 8(1), 54–56.

Rajan, P., Natraj, P., Ranaweera, S. S., Dayarathne, L. A., Lee, Y. J., & Han, C. H. (2022). Anti-adipogenic effect of the flavonoids through the activation of AMPK in palmitate (PA)-treated HepG2 cells. Journal of Veterinary Science, 23(1).

Safe, S., Jayaraman, A., Chapkin, R. S., Howard, M., Mohankumar, K., & Shrestha, R. (2021). Flavonoids: Structure–function and mechanisms of action and opportunities for drug development. Toxicological Research, 37, 147–162.

Saman, H., Raza, S. S., Uddin, S., & Rasul, K. (2020). Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers, 12(5), 1172.

Tao, H., Zhao, Y., Li, L., He, Y., Zhang, X., Zhu, Y., et al. (2023). Comparative metabolomics of flavonoids in twenty vegetables reveal their nutritional diversity and potential health benefits. Food Research International, 164, 112384.

Teekaraman, D., Elayapillai, S. P., Viswanathan, M. P., & Jagadeesan, A. (2019). Quercetin inhibits human metastatic ovarian cancer cell growth and modulates components of the intrinsic apoptotic pathway in PA-1 cell line. Chemico-Biological Interactions, 300, 91–100. https://www.sciencedirect.com/science/article/pii/S0009279718310652

Ullah, A., Munir, S., Badshah, S. L., Khan, N., Ghani, L., Poulson, B. G., et al. (2020). Important flavonoids and their role as a therapeutic agent. Molecules, 25. MDPI AG.

Vaou, N., Stavropoulou, E., Voidarou, C., Tsakris, Z., Rozos, G., Tsigalou, C., et al. (2022). Interactions between medical plant-derived bioactive compounds: Focus on antimicrobial combination effects. Antibiotics, 11(8), 1014.

Villalpando-Rodriguez, G. E., & Gibson, S. B. (2021). Reactive oxygen species (ROS) regulates different types of cell death by acting as a rheostat. Oxidative Medicine and Cellular Longevity, 2021, 1–17.

World Health Organization. (2020). Assessing national capacity for the prevention and control of noncommunicable diseases: Report of the 2019 global survey. Geneva: World Health Organization. Licence: CC BY-NC-SA 3.0 IGO.

Ye, M., Xu, M., Fan, S., Zhang, M., Zhou, B., Yang, S., et al. (2020). Protective effects of three propolis-abundant flavonoids against ethanol-induced injuries in HepG2 cells involving the inhibition of ERK1/2-AHR-CYP1A1 signaling pathways. Journal of Functional Foods, 73, 104087.