Biologia Futura
Volume/Issue:
Volume 70: Issue 4
Sertraline in combination with sorafenib: A promising pharmacotherapy to target both depressive disorders and hepatocellular cancer
Authors:
Zeynep Gunes Ozunal Department of Medical Pharmacology, Faculty of Medicine, Maltepe University, Istanbul, Turkey
Cancer and Stem Cell Research Center (MUKKAM), Maltepe University, Istanbul, Turkey

Search for other papers by Zeynep Gunes Ozunal in
Current site
Google Scholar
PubMed Close
,
Yaprak Donmez Cakil Cancer and Stem Cell Research Center (MUKKAM), Maltepe University, Istanbul, Turkey
Department of Histology and Embryology, Faculty of Medicine, Maltepe University, Istanbul, Turkey

Search for other papers by Yaprak Donmez Cakil in
Current site
Google Scholar
PubMed Close
,
Hatice Isan Cancer and Stem Cell Research Center (MUKKAM), Maltepe University, Istanbul, Turkey

Search for other papers by Hatice Isan in
Current site
Google Scholar
PubMed Close
,
Esra Saglam Department of Medical Pharmacology, Faculty of Medicine, Maltepe University, Istanbul, Turkey

Search for other papers by Esra Saglam in
Current site
Google Scholar
PubMed Close
, and
Ranan Gulhan Aktas Cancer and Stem Cell Research Center (MUKKAM), Maltepe University, Istanbul, Turkey
Department of Histology and Embryology, Faculty of Medicine, Maltepe University, Istanbul, Turkey

Search for other papers by Ranan Gulhan Aktas in
Current site
Google Scholar
PubMed Close
Pages:
341–348
Online Publication Date:
24 Jan 2020
Publication Date:
01 Dec 2019
Article Category:
Research Article
DOI:
https://doi.org/10.1556/019.70.2019.39
Keywords:
sertraline; sorafenib; pharmacotherapy
Restricted access

Introduction

Hepatocellular carcinoma (HCC) is found within the first five most common tumors worldwide. Sorafenib is an approved agent in HCC treatment. Sertraline is a selective serotonin reuptake inhibitor. The aim of the study is to investigate the combination of sertraline and sorafenib at hepatocellular cancer cell proliferation and death.

Methods

HepG2 cells were treated with drugs and viability test XTT was performed. Cells were stained with hematoxylin and eosin for histological examination or with anti-Bcl-2 antibody and Hoechst 33258 for immunofluorescence.

Results

Viability results supported dose-dependent antiproliferative effect for both sertraline and sorafenib. Microscopic evaluation of stained cells exerts morphological changes.

Discussion

This is the first study to show that sorafenib and sertraline have synergistic effect in hepatocellular cancer.

  • Ashburn, T. T. , Thor, K. B. (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683.

    • Search Google Scholar
    • Export Citation

  • Bellmunt, J. , Eisen, T. , Fishman, M. , Quinn, D. (2011) Experience with sorafenib and adverse event management. Crit. Rev. Oncol. Hematol. 78, 24–32.

    • Search Google Scholar
    • Export Citation

  • Bliss, C. I. (1939) The toxicity of poisons applied jointly. Ann. Appl. Biol. 26, 585–615.

  • Cervello, M. , Bachvarov, D. , Lampiasi, N. , Cusimano, A. , Azzolina, A. , McCubrey, J.A. , Montalto, G. (2012) Molecular mechanisms of sorafenib action in liver cancer cells. Cell Cycle 11, 2843–2855.

    • Search Google Scholar
    • Export Citation

  • Chan, H. L. , Chi, W. C. , Chen, V. C. , Huang, K. Y. , Wang, T. N. , Lee, Y. , McIntyre, R. S. , Hsu, T. C. , Lee, C. T. , Tzang, B. S. (2018) SSRIs associated with decreased risk of hepatocellular carcinoma: a population-based case-control study. Psychooncology 27, 187–192.

    • Search Google Scholar
    • Export Citation

  • Chang, C. H. , Chen, S. J. , Liu, C. Y. (2015) Risk of developing depressive disorders following hepatocellular carcinoma: a nationwide population-based study. PLoS One 10, e0135417.

    • Search Google Scholar
    • Export Citation

  • Chen, S. , Xuan, J. , Couch, L. , Iyer, A. , Wu, Y. , Li, Q. Z. , Guo, L. (2014a) Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology 322, 78–88.

    • Search Google Scholar
    • Export Citation

  • Chen, S. , Xuan, J. , Wan, L. , Lin, H. , Couch, L. , Mei, N. , Dobrovolsky, V. N. , Guo, L. (2014b) Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol. Sci. 137, 404–415.

    • Search Google Scholar
    • Export Citation

  • Daher, S. , Massarwa, M. , Benson, A. A., Khoury, T. (2017) Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin. Transl. Hepatol. 6, 69–78.

    • Search Google Scholar
    • Export Citation

  • DeVane, C. L. , Liston, H. L. , Markowitz, J. S. (2002) Clinical pharmacokinetics of sertraline. Clin. Pharmacokinet. 41, 1247–1266.

    • Search Google Scholar
    • Export Citation

  • Fishback, J. A. , Robson, M. J. , Xu, Y. T., Matsumoto, R. R. (2010) Sigma receptors: potential targets for a new class of antidepressant drug. Pharmacol. Ther. 127, 271–282.

    • Search Google Scholar
    • Export Citation

  • Ghouri, Y. A. , Mian, I. , Rowe, J. H. (2017) Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J. Carcinog. 16, 1.

    • Search Google Scholar
    • Export Citation

  • Gil-Ad, I. , Zolokov, A. , Lomnitski, L. , Taler, M., Bar, M., Luria, D., Ram, E., Weizman, A. (2008) Evaluation of the potential anti-cancer activity of the antidepressant sertraline in human colon cancer cell lines and in colorectal cancer-xenografted mice. Int. J Oncol. 33, 277–286.

    • Search Google Scholar
    • Export Citation

  • Hoetelmans, R. , Van Slooten, H. J. , Keijzer, R. , Erkeland, S. , van de Velde, C. J. , Dierendonck, J. H. (2000) Bcl-2 and Bax proteins are present in interphase nuclei of mammalian cells. Cell Death Differ. 7, 384–392.

    • Search Google Scholar
    • Export Citation

  • Ianevski, A. , He, L. , Aittokallio, T. , Tang, J. (2017) SynergyFinder: a web application for analyzing drug combination dose–response matrix data. Bioinformatics 33, 2413–2415.

    • Search Google Scholar
    • Export Citation

  • Huang, J. , Zhao, D. , Liu, Z. , Liu, F. (2018) Repurposing psychiatric drugs as anti-cancer agents. Cancer Lett. 419, 257–265.

  • Joong, S. S. , Liu, J. O. (2014) Recent advances in drug repositioning for the discovery of new anticancer drugs. Int. J. Biol. Sci. 10, 654–663.

    • Search Google Scholar
    • Export Citation

  • Keating, G. M. , Santoro, A. (2009) Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs 69, 223–240.

  • Kuwahara, J. , Takaaki, Y. , Nobuaki, E. , Mitsuyo, U. , Nina, Z. , Soichiro, U. , Satohiro, M. (2015) Comparison of the anti-tumor effects of selective serotonin reuptake inhibitors as well as serotonin and norepinephrine reuptake inhibitors in human hepatocellular carcinoma cells. Biol. Pharm. Bull. 38, 1410–1414.

    • Search Google Scholar
    • Export Citation

  • Liang, C. , Chen, W. , Zhi, X. , Ma, T. , Xia, X. , Liu, H. , Zhang, Q. , Hu, Q. , Hang, Y. , Bai, X. , Liang, T. (2013) Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3a. Mol. Cancer 12, 14.

    • Search Google Scholar
    • Export Citation

  • Ozunal, Z. G. (2014) Drug development, drug repositioning in oncology. In: 19th World Congress on Advances in Oncology and 17th International Symposium on Molecular Medicine, Athens, Greece, October 9–11, 2014.

    • Search Google Scholar
    • Export Citation

  • Patt, Y. , Rojas-Hernandez, C. , Fekrazad, H. M. , Bansal, P. , Lee, F. C. (2017) Phase II trial of sorafenib in combination with capecitabine in patients with hepatocellular carcinoma: INST 08-20. Oncologist 22, 1158–1160.

    • Search Google Scholar
    • Export Citation

  • Peng, L. , Gu, L. , Li, B., Hertz, L. (2014) Fluoxetine and all other SSRIs are 5-HT2B Agonists – importance for their therapeutic effects. Cur. Neuropharmacol. 12, 365–379.

    • Search Google Scholar
    • Export Citation

  • Raza, A. , Sood, G. K. (2014) Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J. Gastroenterol. 20, 4115–4127.

    • Search Google Scholar
    • Export Citation

  • Reddy, K. K. , Lefkove, B. , Chen, L. B. , Govindarajan, B. , Carracedo, A. , Velasco, G. , Carrillo, C. O. , Bhandarkar, S. S. , Owens, M. J. , Mechta-Grigoriou, F. , Arbiser, J. L. (2008) The antidepressant sertraline downregulates Akt and has activity against melanoma cells. Pigment Cell Melanoma Res. 21, 451–456.

    • Search Google Scholar
    • Export Citation

  • Sarrouilhe, D. , Clarhaut, J. , Defamie, N. , Mesnil, M. (2015) Serotonin and cancer: what is the link? Curr. Mol. Med. 15, 62–77.

  • Schrödter, S. , Braun, M. , Syring, I. , Klümper, N. , Deng, M. , Schmidt, D. , Perner, S. , Mülle, R. S. C. , Ellinger, J. (2016) Identification of the dopamine transporter SLC6A3 as a biomarker for patients with renal cell carcinoma. Mol. Cancer 15, 10.

    • Search Google Scholar
    • Export Citation

  • Soll, C. , Riener, M. O. , Oberkofler, C. E. , Hellerbrand, C. , Wild, P. J. , DeOliveira, M. L. , Clavien, P. A. (2012) Expression of serotonin receptors in human hepatocellular cancer. Clin. Cancer Res. 18, 5902–5910.

    • Search Google Scholar
    • Export Citation

  • Tesei, A. , Cortesi, M. , Zamagni, A. , Arienti, C. , Pignatta, S. , Zanoni, M. , Paolillo, M. , Curti, D. , Rui, M. , Rossi, D. , Collina, S. (2018) Sigma receptors as endoplasmic reticulum stress “Gatekeepers” and their modulators as emerging new weapons in the fight against cancer. Front. Pharmacol. 9, 711.

    • Search Google Scholar
    • Export Citation

  • Wei, J. C. , Meng, F. D. , Qu, K. , Wang, Z. X. , Wu, Q. F. , Zhang, L. Q. , Pang, Q. , Liu, C. (2015) Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. Acta Pharmacol. Sin. 36, 241–251.

    • Search Google Scholar
    • Export Citation

  • Xia, D. , Zhang, Y. T. , Xu, G. P. , Yan, W. W. , Pan, X. R. , Tong, J. H. (2017) Sertraline exerts its antitumor functions through both apoptosis and autophagy pathways in acute myeloid leukemia cells. Leukemia & Lymphoma 58, 2208–2217.

    • Search Google Scholar
    • Export Citation

  • Xu, J. J. , Wang, S. Y. , Chen, Y. , Chen, G. P. , Li, Z. Q. , Shao, X. Y. , Li, L. , Lu, W. , Zhou, T. Y. (2014) Dopamine D1 receptor activation induces dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells. Acta Pharmacol. Sin. 35, 889–898.

    • Search Google Scholar
    • Export Citation
  • Collapse
  • Expand
Cover Biologia Futura
Biologia Futura
Print ISSN:
2676-8615
Online ISSN:
2676-8607

To see the editorial board, please visit the website of Springer Nature.

Manuscript Submission: HERE

For subscription options, please visit the website of Springer Nature.

Biologia Futura
Language English
Size A4
Year of
Foundation		 2019 (1950)
Volumes
per Year		 1
Issues
per Year		 4
Founder Magyar Tudományos Akadémia  
Founder's
Address		 H-1051 Budapest, Hungary, Széchenyi István tér 9.
Publisher Akadémiai Kiadó
Springer Nature Switzerland AG
Publisher's
Address		 H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
CH-6330 Cham, Switzerland Gewerbestrasse 11.
Responsible
Publisher		 Chief Executive Officer, Akadémiai Kiadó
ISSN 2676-8615 (Print)
ISSN 2676-8607 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Dec 2024 39 0 0
Jan 2025 65 0 0
Feb 2025 89 0 0
Mar 2025 83 0 0
Apr 2025 39 0 0
May 2025 44 0 0
Jun 2025 31 0 0