Effects of sertraline and sorafenib on HepG2 cells with a possible link to autophagy

Demirel,Gamze; Pinarer,Nil; Ergin,Mert Emre; Saraçoğlu,Zeynep; Bingöl,Ceren; Özünal,Zeynep Güneş; Dönmez Çakil,Yaprak

doi:10.3892/mi.2025.246

Effects of sertraline and sorafenib on HepG2 cells with a possible link to autophagy

Authors:
- Gamze Demirel
- Nil Pinarer
- Mert Emre Ergin
- Zeynep Saraçoğlu
- Ceren Bingöl
- Zeynep Güneş Özünal
- Yaprak Dönmez Çakil
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Affiliations: Cancer and Stem Cell Center, Maltepe University, 34858 Istanbul, Türkiye, Faculty of Medicine, Maltepe University, 34858 Istanbul, Türkiye, Department of Medical Pharmacology, Faculty of Medicine, Atlas University, 34403 Istanbul, Türkiye, Department of Medical Biology and Genetics, Faculty of Medicine, Maltepe University, 34858 Istanbul, Türkiye
Published online on: May 29, 2025 https://doi.org/10.3892/mi.2025.246
Article Number: 47
Copyright : © Demirel et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Liver cancer is one of the leading causes of cancer‑related mortality worldwide. The current range of treatment options for patients with advanced‑stage disease, including the first approved systemic therapy, sorafenib, has been demonstrated to have limited efficacy. A significant number of patients develop resistance to sorafenib treatment or discontinue its use due to adverse effects. Depression is a common complication of cancer, and the antidepressant, sertraline, has recently garnered considerable attention due to its anticancer activity. Accumulating evidence suggests that autophagy may represent a highly promising target for cancer therapy. Previously, the authors demonstrated that the sorafenib and sertraline combination exerted a synergistic anticancer effect on HepG2 cells. The present study examined the intracellular localization and mRNA expression levels of key autophagy markers, including Beclin‑1, p62 and LC3, as well as the formation of acidic vesicular organelles using acridine orange staining, to further elucidate the link between autophagy and combined treatment of HepG2 cancer cells with sorafenib and sertraline. Drug treatment did not result in significant alterations in the expression levels of the LC3 and Beclin‑1 genes. However, following treatment with sertraline, sorafenib, or both, the development of acidic vesicular organelles and the noticeable formation of LC3 and p62 puncta demonstrated the induction of changes related to autophagic activity. On the whole, the results of the present study support the effects of sertraline and sorafenib, which may, at least in part, be linked to autophagy.

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1	Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I and Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 74:229–263. 2024.PubMed/NCBI View Article : Google Scholar
2	Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, Wang Q, Wang S, Rong D, Reiter FP, et al: The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 5(87)2020.PubMed/NCBI View Article : Google Scholar
3	Liu J, Xia S, Zhang B, Mohammed DM, Yang X, Zhu Y and Jiang X: Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: Recent advances and future perspectives. Discov Oncol. 15(259)2024.PubMed/NCBI View Article : Google Scholar
4	Zarlashat Y, Abbas S and Ghaffar A: Hepatocellular carcinoma: Beyond the border of advanced stage therapy. Cancers (Basel). 16(2034)2024.PubMed/NCBI View Article : Google Scholar
5	Baú-Carneiro JL, Akemi Guirao Sumida I, Gallon M, Zaleski T, Boia-Ferreira M and Bridi Cavassin F: Sertraline repositioning: An overview of its potential use as a chemotherapeutic agent after four decades of tumor reversal studies. Transl Oncol. 16(101303)2022.PubMed/NCBI View Article : Google Scholar
6	Jiang X, Lu W, Shen X, Wang Q, Lv J, Liu M, Cheng F, Zhao Z and Pang X: Repurposing sertraline sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight. 3(e98921)2018.PubMed/NCBI View Article : Google Scholar
7	Xia D, Zhang YT, Xu GP, Yan WW, Pan XR and Tong JH: Sertraline exerts its antitumor functions through both apoptosis and autophagy pathways in acute myeloid leukemia cells. Leuk Lymphoma. 58:1–10. 2017.PubMed/NCBI View Article : Google Scholar
8	Telerman A, Tuynder M, Dupressoir T, Robaye B, Sigaux F, Shaulian E, Oren M, Rommelaere J and Amson R: A model for tumor suppression using H-1 parvovirus. Proc Natl Acad Sci USA. 90:8702–8706. 1993.PubMed/NCBI View Article : Google Scholar
9	Sun T, Liu H and Ming L: Multiple roles of autophagy in the sorafenib resistance of hepatocellular carcinoma. Cell Physiol Biochem. 44:716–727. 2017.PubMed/NCBI View Article : Google Scholar
10	Elleithi Y, El-Gayar A and Amin MN: Autophagy modulation attenuates sorafenib resistance in HCC induced in rats. Cell Death Dis. 15(595)2024.PubMed/NCBI View Article : Google Scholar
11	Gómez-Virgilio L, Silva-Lucero MD, Flores-Morelos DS, Gallardo-Nieto J, Lopez-Toledo G, Abarca-Fernandez AM, Zacapala-Gómez AE, Luna-Muñoz J, Montiel-Sosa F, Soto-Rojas LO, et al: Autophagy: A key regulator of homeostasis and disease: An overview of molecular mechanisms and modulators. Cells. 11(2262)2022.PubMed/NCBI View Article : Google Scholar
12	Zhang K, Zhang Q, Jia R, Xiang S and Xu L: A comprehensive review of the relationship between autophagy and sorafenib-resistance in hepatocellular carcinoma: Ferroptosis is noteworthy. Front Cell Dev Biol. 11(1156383)2023.PubMed/NCBI View Article : Google Scholar
13	Hwang HY, Shim JS, Kim D and Kwon HJ: Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein. Autophagy. 17:2783–2799. 2021.PubMed/NCBI View Article : Google Scholar
14	Zinnah KMA, Seol JW and Park SY: Inhibition of autophagy flux by sertraline attenuates TRAIL resistance in lung cancer via death receptor 5 upregulation. Int J Mol Med. 46:795–805. 2020.PubMed/NCBI View Article : Google Scholar
15	Ozunal ZG, Cakil YD, Isan H, Saglam E and Aktas RG: Sertraline in combination with sorafenib: A promising pharmacotherapy to target both depressive disorders and hepatocellular cancer. Biol Futur. 70:341–348. 2019.PubMed/NCBI View Article : Google Scholar
16	Chen R, Zou Y, Mao D, Sun D, Gao G, Shi J, Liu X, Zhu C, Yang M, Ye W, et al: The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation. J Cell Biol. 206:173–182. 2014.PubMed/NCBI View Article : Google Scholar
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
18	Ladd AD, Duarte S, Sahin I and Zarrinpar A: Mechanisms of drug resistance in HCC. Hepatology. 79:926–940. 2024.PubMed/NCBI View Article : Google Scholar
19	Zhu YJ, Zheng B, Wang HY and Chen L: New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 38:614–622. 2017.PubMed/NCBI View Article : Google Scholar
20	Duarte D and Vale N: Antidepressant drug sertraline against human cancer cells. Biomolecules. 12(1513)2022.PubMed/NCBI View Article : Google Scholar
21	Mizushima N, Levine B, Cuervo AM and Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 451:1069–1075. 2008.PubMed/NCBI View Article : Google Scholar
22	Parkhitko AA, Favorova OO and Henske EP: Autophagy: Mechanisms, regulation, and its role in tumorigenesis. Biochemistry (Mosc). 78:355–367. 2013.PubMed/NCBI View Article : Google Scholar
23	Li X, He S and Ma B: Autophagy and autophagy-related proteins in cancer. Mol Cancer. 19(12)2020.PubMed/NCBI View Article : Google Scholar
24	White E and DiPaola RS: The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 15:5308–5316. 2009.PubMed/NCBI View Article : Google Scholar
25	Runwal G, Stamatakou E, Siddiqi FH, Puri C, Zhu Y and Rubinsztein DC: LC3-positive structures are prominent in autophagy-deficient cells. Sci Rep. 9(10147)2019.PubMed/NCBI View Article : Google Scholar
26	Cohen-Kaplan V, Ciechanover A and Livneh I: p62 at the crossroad of the ubiquitin-proteasome system and autophagy. Oncotarget. 7:83833–83834. 2016.PubMed/NCBI View Article : Google Scholar
27	Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Øvervatn A, Bjørkøy G and Johansen T: p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 282:24131–24145. 2007.PubMed/NCBI View Article : Google Scholar
28	Yoshii SR and Mizushima N: Monitoring and measuring autophagy. Int J Mol Sci. 18(1865)2017.PubMed/NCBI View Article : Google Scholar
29	Pugsley HR: Assessing autophagic flux by measuring LC3, p62, and LAMP1 Co-localization using multispectral imaging flow cytometry. J Vis Exp. 21(55637)2017.PubMed/NCBI View Article : Google Scholar
30	He L, Fu Y, Tian Y, Wang X, Zhou X, Ding RB, Qi X and Bao J: Antidepressants as autophagy modulators for cancer therapy. Molecules. 28(7594)2023.PubMed/NCBI View Article : Google Scholar
31	Thomé MP, Filippi-Chiela EC, Villodre ES, Migliavaca CB, Onzi GR, Felipe KB and Lenz G: Ratiometric analysis of acridine orange staining in the study of acidic organelles and autophagy. J Cell Sci. 129:4622–4632. 2016.PubMed/NCBI View Article : Google Scholar
32	Chinnapaka S, Bakthavachalam V and Munirathinam G: Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: Dual activation of apoptosis and autophagy signaling by deregulating redox balance. Am J Cancer Res. 10:2043–2065. 2020.PubMed/NCBI