The effect of Epigallocatechin-3-Gallate (EGCG) combined with low dose sorafenib in apoptosis and Platelet-Derived Growth Factor Receptor (PDGFR) expression in hepatocellular carcinoma rats

Emilia Rosita; Sigit Adi Prasetyo; Ignasius Riwanto; Wahyuni Lukita Atmodjo

doi:10.15562/bmj.v11i1.2985

The effect of Epigallocatechin-3-Gallate (EGCG) combined with low dose sorafenib in apoptosis and Platelet-Derived Growth Factor Receptor (PDGFR) expression in hepatocellular carcinoma rats

Emilia Rosita ,

Sigit Adi Prasetyo ,

Ignasius Riwanto ,

Wahyuni Lukita Atmodjo ,

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DOI: https://doi.org/10.15562/bmj.v11i1.2985 |
Published: 2022-04-13

Abstract

Background: Sorafenib is a targeting therapy in Hepatocellular carcinoma (HCC) that targets Vascular Endothelial Growth Factor Receptors 1 (VEGFR-1), VEGFR-2, and VEGFR-3; Platelet-Derived Growth Factor Receptors β (PDGFR-β); c-Kit proto-oncogenes; FLT-3 genes; RET proto-oncogenes; and Raf-1 genes that have the same function in suppressing tumor cell proliferation, angiogenesis, and promotes tumor cell apoptosis; but its high cost makes necessary to reduce the dosage by combining with other agents. Epigallocatechin-3-Gallate (EGCG) has great potential in cancer treatment because of its anti-angiogenesis, induced apoptosis, and low cost. This study aimed to examine the effects of combination EGCG with low dose sorafenib compared to standard dose sorafenib in apoptosis and PDGFR expression in HCC rats

Methods: Twenty-five male Wistar rats were randomly assigned into 4 groups: sham, control, EGCG+low dose sorafenib, and standard-dose sorafenib. Diethylnitrosamine (DEN) injection to induce HCC was carried out to all Wistar rats except for the sham group. After HCC was developed, the EGCG+low dose sorafenib group and standard-dose sorafenib group received the administration of the drugs for two weeks. PDGFR expression and apoptotic index were assessed in the last 3 groups. Data were analyzed using SPSS version 20 for Windows.

Results: There was a non-significant difference of mean PDGFR expression level between the EGCG+low dose sorafenib group and standard-dose sorafenib group (p>0.05); however, there was a lower significant difference of both groups compared to the control group (p<0.05). There was a non-significant difference of apoptotic index between low dose sorafenib+EGCG group and standard-dose sorafenib group (p>0.05); in addition, there were a higher not significantly different of both groups compared to the control group (p>0.05).

Conclusion: Combining low dose sorafenib with EGCG has a comparable effect with standard-dose sorafenib in reducing PDGFR of HCC, but not for apoptosis.

References

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941-1953.
Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, et al. The Role of Angiogenesis in Hepatocellular Carcinoma. Clin Cancer Res. 2019;25(3):912-920.
Arfianti, Putra ZD, Delhaldita E, Sembiring LP, Asputra H. Viral and non-viral causes in patients with hepatocellular carcinoma in Arifin Achmad General Hospital, Riau Province during 2013-2017. Bali Medical Journal. 2019;8(3):759-763.
García ER, Gutierrez EA, de Melo FCSA, Novaes RD, Gonçalves RV. Flavonoids Effects on Hepatocellular Carcinoma in Murine Models: A Systematic Review. Evid Based Complement Alternat Med. 2018;2018:6328970.
Atmodjo WL, Larasati YO, Isbandiati D, Mathew G1. Curcuminoids Suppress the Number of Transformed-Hepatocytes and Ki67 Expression in Mice Liver Carcinogenesis Induced by Diethylnitrosamine. Journal of Science and Research 2018,3(2):1-6.
Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017;38(5):614-622.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25-34.
Xu H, Becker CM, Lui WT, Chu CY, Davis TN, Kung AL, et al. Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. Fertil Steril. 2011;96(4):1021-1028.
Nishikawa T, Nakajima T, Moriguchi M, Jo M, Sekoguchi S, Ishii M, et al. A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins. J Hepatol. 2006;44(6):1074-1082.
Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12:86.
Bimonte S, Albino V, Piccirillo M, Nasto A, Molino C, Palaia R, et al. Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: experimental findings and translational perspectives. Drug Des Devel Ther. 2019;13:611-621.
Li S, Wu L, Feng J, Li J, Liu T, Zhang R, et al. In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity. Sci Rep. 2016;6:28479.
Sakata R, Ueno T, Nakamura T, Sakamoto M, Torimura T, Sata M. Green tea polyphenol epigallocatechin-3-gallate inhibits platelet-derived growth factor-induced proliferation of human hepatic stellate cell line LI90. J Hepatol. 2004;40(1):52-59.
Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res. 2018;79(8):373-382.
Turner PV, Brabb T, Pekow C, Vasbinder MA. Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci. 2011;50(5):600-613.
Arifin WN, Zahiruddin WM. Sample Size Calculation in Animal Studies Using Resource Equation Approach. Malays J Med Sci. 2017;24(5):101-105.
Tolba R, Kraus T, Liedtke C, Schwarz M, Weiskirchen R. Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Lab Anim. 2015;49(1 Suppl):59-69.
Soini Y, Pääkkö P, Lehto VP. Histopathological evaluation of apoptosis in cancer. Am J Pathol. 1998;153(4):1041-1053.
Yasuda Y, Shimizu M, Sakai H, Iwasa J, Kubota M, Adachi S, et al. (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. Chem Biol Interact. 2009;182(2-3):159-64.
Tamura K, Nakae D, Horiguchi K, Akai H, Kobayashi Y, Satoh H, et al. Inhibition by green tea extract of diethylnitrosamine-initiated but not choline-deficient, L-amino acid-defined diet-associated development of putative preneoplastic, glutathione S-transferase placental form-positive lesions in rat liver. Jpn J Cancer Res. 1997;88(4):356-62.
Nishida H, Omori M, Fukutomi Y, Ninomiya M, Nishiwaki S, Suganuma M, et al. Inhibitory effects of (-)-epigallocatechin gallate on spontaneous hepatoma in C3H/HeNCrj mice and human hepatoma-derived PLC/PRF/5 cells. Jpn J Cancer Res. 1994;85(3):221-225.
Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011;82(12):1807-1821.
Marisi G, Cucchetti A, Ulivi P, Canale M, Cabibbo G, Solaini L, et al. Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers? World J Gastroenterol. 2018;24(36):4152-4163.