Citrus pectin oligomers in combination with cisplatin enhances apoptosis in HepG2 human hepatocellular carcinoma cells Citrus pectin oligomers enhances apoptosis in HepG2…
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Abstract
Pectin is a widely used gelling agent in food, primarily composed of polygalacturonic acid. Cisplatin (DDP), a commonly used chemotherapeutic agent, has significant side effects, which necessitate efforts to reduce its usage. One approach to mitigate these side effects involves combining cisplatin with food-based bioactive compounds, such as oligogalacturonides (OGA) - shorter chain derivatives of pectin. In the present study, synergistic suppressive effects of OGA and DDP on hepatocellular carcinoma (HCC) cells were determined. HepG2 cells were treated with OGA (100 µg.ml-1) and DDP (2 µg.ml-1) in different combinations. Assays for cell viability, morphology, lactate dehydrogenase activity, cell cycle, apoptosis, western blot, galectin-3, and comet analysis were performed. Compared to DDP treatment, 55% reduction of IC50 values in the cell viability of HepG2 cells treated with DDP 12h + OGA 12h was observed. OGA-DDP combined showed the cell cycle arrest in G2/M, increased the galectin-3 release, and decreased the mitochondrial membrane permeability (MMP) significantly (p<0.05). Western blot study showed the upregulation of Bax, p53, and Caspase-3, and the downregulation of Bcl-2 proteins (p<0.05) by OGA and DDP combination treatment. These findings suggest that OGA-DDP enhances cisplatin’s anticancer efficacy while potentially reducing its required dosage, offering a promising strategy for improving HCC treatment outcomes.
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Alshehri B. Cytochrome C and cancer cell metabolism: A new perspective. Saudi Pharmaceutical Journal, 2024, 32(12): 102194. https://doi.org/10.1016/j.jsps.2024.102194
Bennukul K., Numkliang S., Leardkamolkarn V. Melatonin attenuates cisplatin-induced HepG2 cell death via the regulation of mTOR and ERCC1 expressions. World Journal of Hepatology, 2014, 6(4): 230. https://doi.org/10.4254/wjh.v6.i4.230
Bergman M., Djaldetti M., Salman H., Bessler H. Effect of citrus pectin on malignant cell proliferation. Biomedicine and Pharmacotherapy, 2010, 64(1): 44-47. https://doi.org/10.1016/j.biopha.2009.03.004
Bruix J., Chan S.L., Galle P.R., Rimassa L., Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. Journal of Hepatology, 2021, 75(4): 960-974. https://doi.org/10.1016/j.jhep.2021.07.004
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Chen Z., Xie H., Hu M., Huang T., Hu Y., Sang N., Zhao Y. Recent progress in treatment of hepatocellular carcinoma. American Journal of Cancer Research, 2020, 10(9): 2993-3306. Available at: https://e-century.us/files/ajcr/10/9/ajcr0116653.pdf
Díaz-Alvarez L., Ortega E. The many roles of Galectin-3, a multifaceted molecule, in innate immune responses against pathogens. Mediators of Inflammation, 2017(5): 9247574. https://doi.org/10.1155/2017/9247574
Ding W.X., Li M., Chen X., Ni H.M., Lin C.W., Gao W., Lu B., Stolz D.B. Clemens D.L., Yin X.M. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology, 2010, 139(5): 1740-1752. https://doi.org/10.1053/j.gastro.2010.07.041
Galluzzi L., Senovilla L., Vitale I., Michels J., Martins I., Kepp O., Castedo M., Kroemer G. Molecular mechanisms of cisplatin resistance. Oncogene, 2012, 31(9): 1869-1883. https://doi.org/10.1038/onc.2011.384
Gerets H., Tilmant K., Gerin B., Chanteux H., Depelchin B., Dhalluin S., Atienzar F. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biology and Toxicology, 2012, 28(1): 69-87. https://doi.org/10.1007/s10565-011-9208-4
Hamaya S., Oura K., Morishita A., Masaki T. Cisplatin in Liver Cancer Therapy. International Journal of Molecular Sciences, 2023, 24(13): 10858. https://doi.org/10.3390/ijms241310858
Huang C.S., Huang A.C., Huang P.H., Lo D., Wang Y.T., Wu M.C. Synergistic antitumor effect of oligogalacturonides and cisplatin on human lung cancer A549 cells. International Journal of Molecular Sciences, 2018, 19(6): 1769. https://doi.org/10.3390/ijms19061769
Huang P.H., Lu H.T., Wang Y.T., Wu M.C. Antioxidant activity and emulsion-stabilizing effect of pectic enzyme treated pectin in soy protein isolate-stabilized oil/water emulsion. Journal of Agricultural and Food Chemistry, 2011, 59(17): 9623-9628. https://doi.org/10.1021/jf202020t
Huang P.H., Fu L.C., Huang C.S., Wang Y.T., Wu M.C. The uptake of oligogalacturonide and its effect on growth inhibition, lactate dehydrogenase activity and galactin-3 release of human cancer cells. Food Chemistry, 2012, 132(4): 1987-1995. https://doi.or g/10.1016/j.foodchem.2011.12.037
Ikeda M., Morizane C., Ueno M., Okusaka T., Ishii H., Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Japanese Journal of Clinical Oncology 2018, 48(2): 103-114. https://doi.org/10.1093/jjco/hyx180
Liskova A., Koklesova L., Samec M., Smejkal K., Samuel S.M., Varghese E., Abotaleb M., Biringer K., Kudela E., Danko J., Shakibaei M., Kwon T.K., Büsselberg D., Kubatka P. Flavonoids in cancer metastasis. Cancers, 2020, 12(6): 1498. https://doi.org/10.1016/j.foodchem.2011.12.037
Ma X., Zhang Y., Guan M., Zhang W., Tian H., Jiang C., Tan X., Kang W. Genotoxicity of chloroacetamide herbicides and their metabolites in vitro and in vivo. International Journal of Molecular Medicine, 2021, 47(6): 1-10. https://doi.org/10.3892/ijmm.2021.4936
Mendonça L.M., dos Santos G.C., dos Santos R.A., Takahashi C.S., Bianchi M., Antunes L. Evaluation of curcumin and cisplatin-induced DNA damage in PC 12 cells by the alkaline comet assay. Human and Experimental Toxicology, 2010, 29(1): 635-643. https://doi.org/10.1177/0960327109358731
Mueller S., Schittenhelm M., Honecker F., Malenke E., Lauber K., Wesselborg S., Hartmann J.T., Bokemeyer C., Mayer F. Cell-cycle progression and response of germ cell tumors to cisplatin in vitro. International Journal of Oncology, 2006, 29(2): 471-479. https://doi.org/10.3892/ijo.29.2.471
Mukhopadhyay A., Dutta N., Chattopadhyay D., Chakrabarti K. Degumming of ramie fiber and the production of reducing sugars from waste peels using nanoparticle supplemented pectate lyase. Bioresource Technology, 2013, 137(6): 202-208. https://doi.org/10.1016/j.biortech.2013.03.139
Olsson M., Zhivotovsky B. Caspases and cancer. Cell Death and Differentiation, 2011, 18(4): 1441-1449. https://doi.org/10.1038/cdd.2011.30
Osaki A., Suda T., Kamimura K., Tsuchiya A., Tamura Y., Takamura M., Igarashi M., Kawai H., Yamagiwa S., Aoyagi Y. A safe and effective dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma. Cancer medicine, 2013, 2(1): 86-98. https://doi.org/10.1002/cam4.55
Pietro A., Koster R., Boersma-van E.W., Dam W.A., Mulder N.H., Gietema J.A., Vries E.G.E., Jong S. Pro- and anti-apoptotic effects of p53 in cisplatin-treated human testicular cancer are cell context-dependent. Cell Cycle, 2012, 11(24): 4552-4562. https://doi.org/10.4161/cc.22803
Saffroy R., Pham P., Lemoine A., Debuire B. Molecular biology and hepatocellular carcinoma: current status and future prospects. Annales de Biologie Clinique, 2004, 62(6): 649-656. Available at: https://pubmed.ncbi.nlm.nih.gov/15563423/
Shi Z-D., Pang K., Wu Z-X., Dong Y., Hao L., Qin J-X., Wang W., Chen Z-S., Han C-H. Tumor cell plasticy in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduction and Targeted Therapy, 2023, 8(113): 1-21. https://doi.org/10.1038/s41392-023-01383-x
Tait S.W.G., Green D.R. Mitochondria and cell signalling. Journal of Cell Science, 2010, 125(4): 519-525. https://doi.org/10.1242/jcs.099234
Tan E.Y., Danpanichkul P., Yong J.N., Yu Z., Tan D.J.H., Lim W.H., Koh B., Lim R.Y.Z., Tham E.K.J., Mitra K., Morishita A., Hsu Y-C., Yang J.D., Takahashi H., Zheng M-H., Nakajima A., Ng C.H., Wijarnpreecha K., Wijarnpreecha K., Muthiah M.D., Singal A.G., Huang D.Q. Liver cancer in 2021: Global burden of disease study. Journal of Hepatology, 2024, 82(5): 851-860. https://doi.org/10.1016/j.jhep.2024.10.031
Tchounwou P.B., Dasari S., Noubissi F.K, Ray P., Kumar S. Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy. Journal of Experimental Pharmacology, 2021-13(3): 303-328. https://doi.org/10.2147/jep.s267383
Venook A.P., Papandreou C., Furuse J., Ladrón de Guevara L. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. The Oncologist, 2010, 15(S4): 5-13. https://doi.org/10.1634/theoncologist.2010-s4-05
Waller L.P., Deshpande V., Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World Journal of Hepatology, 2015, 7(26): 2648. https://doi.org/10.4254/wjh.v7.i26.2648
Wang Y., Liu Y., Liu Y., Zhou W., Wang H., Wan G., Sun D., Zhang N., Wang Y. A polymeric prodrug of cisplatin based on pullulan for the targeted therapy against hepatocellular carcinoma. International Journal of Pharmaceutics, 2015, 483(1-2): 89-100. https://doi.org/10.1016/j.ijpharm.2015.02.027
Wu X., Fu J., Mei R., Dai X., Li J., Zhao X., Liu M. Inhibition of liver cancer HepG2 cell proliferation by enzymatically prepared low-molecular citrus pectin. Current Pharmaceutical Biotechnology, 2022, 23(6): 861-872. https://doi.org/10.2174/1389201022666210729122631
Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nature Reviews Gastroenterology & Hepatology, 2019, 16(8): 589-604. https://doi.org/10.1038/s41575-019-0186-y
Yang X., Xie X., Xiao Y.F., Xie R., Hu C.J., Tang B., Li B.S., Yang S.M. The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma. Cancer Letter, 2015, 360(2): 119-124. https://doi.org/10.1016/j.canlet.2015.02.035
Yin Q., Wu L., Han L., Zheng X., Tong R., Li L., Bai L., Bian Y. Immune-related adverse events of immune checkpoint inhibitors: a review. Frontiers in Immunology, 2023, 25(14): 1167975. https://doi.org/10.3389/fimmu.2023.1167975
Zhang W., Xu P., Zhang H. Pectin in cancer therapy: A review. Trends in Food Science & Technology, 2015, 44(2): 258-271. https://doi.org/10.1016/j.tifs.2015.04.001
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How to Cite
HUANG, Cian-Song et al.
Citrus pectin oligomers in combination with cisplatin enhances apoptosis in HepG2 human hepatocellular carcinoma cells.
Food Science and Applied Biotechnology, [S.l.], v. 8, n. 2, p. 251-263, oct. 2025.
ISSN 2603-3380.
Available at: <https://www.ijfsab.com/index.php/fsab/article/view/455>. Date accessed: 18 feb. 2026.
doi: https://doi.org/10.30721/fsab2025.v8.i2.455.