Gossypol Enhances Ponatinib's Cytotoxicity Against Human Hepatocellular Carcinoma Cells by Involving Cell Cycle Arrest, P-AKT/LC3II/p62, and Bcl2/caspase-3 Pathways

Overview

Journal Toxicol Rep

Date 2025 Jan 13

PMID 39802605

Authors

Hadeel H Elkattan

Alaa E Elsisi

Naglaa M El-Lakkany

Affiliations

Soon will be listed here.

Abstract

Despite significant breakthroughs in frontline cancer research and chemotherapy for hepatocellular carcinoma (HCC), many of the suggested drugs have high toxic side effects and resistance, limiting their clinical utility. Exploring potential therapeutic targets or novel combinations with fewer side effects is therefore crucial in combating this dreadful disease. The current study aims to use a novel combination of ponatinib and gossypol against the HepG2 cell line. Cell survival, FGF19/FGFR4, apoptotic and autophagic cell death, and synergistic drug interactions were assessed in response to increasing concentrations of ponatinib and/or gossypol treatment. Research revealed that ponatinib (1.25-40 μM) and gossypol (2.5-80 μM) reduced the viability of HepG2 cells in a way that was dependent on both time and dose. Ponatinib's anti-proliferation effectiveness was improved synergistically by gossypol and was associated with a rise in apoptotic cell death, cell cycle blockage during the G0/G1 phase, and suppression of the FGF19/FGFR4 axis. Furthermore, the ponatinib/gossypol combination lowered Bcl-2 and p-Akt while increasing active caspase-3, Beclin-1, p62, and LC3II. This combination, however, had no harm on normal hepatocytes. Overall, gossypol enhanced ponatinib's anticancer effects in HCC cells. Notably, this new combination appears to be potential adjuvant targeted chemotherapy, a discovery that warrants more clinical investigation, in the management of patients with HCC.

References

Lee S, Hong E, Jo E, Kim Z, Yim K, Woo S . Gossypol Induces Apoptosis of Human Pancreatic Cancer Cells via CHOP/Endoplasmic Reticulum Stress Signaling Pathway. J Microbiol Biotechnol. 2022; 32(5):645-656. PMC: 9628887. DOI: 10.4014/jmb.2110.10019. View

Wilson T, McEwan M, McLaughlin K, Le Clorennec C, Allen W, Fennell D . Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells. Oncogene. 2008; 28(1):63-72. DOI: 10.1038/onc.2008.366. View

Li X, Yang K, Chen W, Mai J, Wu X, Sun T . CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy. 2021; 17(12):4323-4340. PMC: 8726624. DOI: 10.1080/15548627.2021.1912270. View

Lian J, Wu X, He F, Karnak D, Tang W, Meng Y . A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ. 2010; 18(1):60-71. PMC: 2950895. DOI: 10.1038/cdd.2010.74. View

Bayat Mokhtari R, Homayouni T, Baluch N, Morgatskaya E, Kumar S, Das B . Combination therapy in combating cancer. Oncotarget. 2017; 8(23):38022-38043. PMC: 5514969. DOI: 10.18632/oncotarget.16723. View

Ali Shah S, Hassan S, Bungau S, Si Y, Xu H, Rahman M . Chemically Diverse and Biologically Active Secondary Metabolites from Marine . Mar Drugs. 2020; 18(10). PMC: 7601752. DOI: 10.3390/md18100493. View

Mortezaee K, Najafi M, Farhood B, Ahmadi A, Potes Y, Shabeeb D . Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review. Life Sci. 2019; 228:228-241. DOI: 10.1016/j.lfs.2019.05.009. View

Turkington R, Longley D, Allen W, Stevenson L, McLaughlin K, Dunne P . Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell Death Dis. 2014; 5:e1046. PMC: 3944229. DOI: 10.1038/cddis.2014.10. View

Xiong J, Li J, Yang Q, Wang J, Su T, Zhou S . Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer. Breast Cancer Res. 2017; 19(1):27. PMC: 5343402. DOI: 10.1186/s13058-017-0818-5. View

10.

Brentnall M, Rodriguez-Menocal L, De Guevara R, Cepero E, Boise L . Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 2013; 14:32. PMC: 3710246. DOI: 10.1186/1471-2121-14-32. View

11.

Lee Y, Lee J . Role of the mammalian ATG8/LC3 family in autophagy: differential and compensatory roles in the spatiotemporal regulation of autophagy. BMB Rep. 2016; 49(8):424-30. PMC: 5070729. DOI: 10.5483/bmbrep.2016.49.8.081. View

12.

Song C, Han Y, Luo H, Qin Z, Chen Z, Liu Y . HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer. Cancer Med. 2019; 8(12):5651-5661. PMC: 6745829. DOI: 10.1002/cam4.2440. View

13.

Deng Q, Wang Z, Wang L, Zhang L, Xiang X, Wang Z . Lower mRNA and protein expression levels of LC3 and Beclin1, markers of autophagy, were correlated with progression of renal clear cell carcinoma. Jpn J Clin Oncol. 2013; 43(12):1261-8. DOI: 10.1093/jjco/hyt160. View

14.

Islam M, Sooro M, Zhang P . Autophagic Regulation of p62 is Critical for Cancer Therapy. Int J Mol Sci. 2018; 19(5). PMC: 5983640. DOI: 10.3390/ijms19051405. View

15.

Yamaoka T, Kusumoto S, Ando K, Ohba M, Ohmori T . Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci. 2018; 19(11). PMC: 6274851. DOI: 10.3390/ijms19113491. View

16.

Corallo D, Pastorino F, Pantile M, Mariotto E, Caicci F, Viola G . Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib. J Exp Clin Cancer Res. 2020; 39(1):195. PMC: 7507635. DOI: 10.1186/s13046-020-01692-x. View

17.

Sivasankarapillai V, Madhu Kumar Nair R, Rahdar A, Bungau S, Zaha D, Aleya L . Overview of the anticancer activity of withaferin A, an active constituent of the Indian ginseng Withania somnifera. Environ Sci Pollut Res Int. 2020; 27(21):26025-26035. DOI: 10.1007/s11356-020-09028-0. View

18.

Hu L, Cong L . Fibroblast growth factor 19 is correlated with an unfavorable prognosis and promotes progression by activating fibroblast growth factor receptor 4 in advanced-stage serous ovarian cancer. Oncol Rep. 2015; 34(5):2683-91. DOI: 10.3892/or.2015.4212. View

19.

Yurekli B, Karaca B, Kisim A, Bozkurt E, Atmaca H, Cetinkalp S . AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells. J Endocrinol Invest. 2017; 41(2):233-240. DOI: 10.1007/s40618-017-0733-8. View

20.

Wilkening S, Bader A . Influence of culture time on the expression of drug-metabolizing enzymes in primary human hepatocytes and hepatoma cell line HepG2. J Biochem Mol Toxicol. 2003; 17(4):207-13. DOI: 10.1002/jbt.10085. View