Growth inhibition and transcriptional effects of ribavirin in lymphoma

Dominguez‑Gomez,Guadalupe; Cortez‑Pedroza,Dominique; Chavez‑Blanco,Alma; Taja‑Chayeb,Lucia; Hidalgo‑Miranda,Alfredo; Cedro‑Tanda,Alberto; Beltran‑Anaya,Fredy; Diaz‑Chavez,Jose; Schcolnik‑Cabrera,Alejandro; Gonzalez‑Fierro,Aurora; Dueñas‑Gonzalez,Alfonso

doi:10.3892/or.2019.7240

Growth inhibition and transcriptional effects of ribavirin in lymphoma

Authors:
- Guadalupe Dominguez‑Gomez
- Dominique Cortez‑Pedroza
- Alma Chavez‑Blanco
- Lucia Taja‑Chayeb
- Alfredo Hidalgo‑Miranda
- Alberto Cedro‑Tanda
- Fredy Beltran‑Anaya
- Jose Diaz‑Chavez
- Alejandro Schcolnik‑Cabrera
- Aurora Gonzalez‑Fierro
- Alfonso Dueñas‑Gonzalez
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Affiliations: Division of Basic Research, National Cancer Institute (INCAN), Mexico City 14080, Mexico, Cancer Genomics Laboratory, National Institute of Genomic Medicine (INMEGEN), Mexico City 14610, Mexico, Unit of Biomedical Research, Institute of Biomedical Research, National Autonomous University of Mexico (UNAM)/INCAN, Mexico City 14080, Mexico
Published online on: July 17, 2019 https://doi.org/10.3892/or.2019.7240
Pages: 1248-1256

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Abstract

Ribavirin exhibits inhibitory effects on the epigenetic enzyme enhancer of zeste homolog 2 (EZH2), which participates in lymphomagenesis. Additionally, preclinical and clinical studies have demonstrated the anti‑lymphoma activity of this drug. To further investigate the potential of ribavirin as an anticancer treatment for lymphoma, the tumor‑suppressive effects of ribavirin were analyzed in lymphoma cell lines. The effects of ribavirin on the viability and clonogenicity of the B‑cell lymphoma cell line Pfeiffer (EZH2‑mutant), Toledo (EZH2 wild‑type) and cutaneous T‑cell lymphoma Hut78 cell line were assessed. Expression of EZH2 and trimethylation status of histone 3, lysine 27 trimethylated (H3K27m3) was also determined in response to ribavirin. The transcriptional effects of ribavirin on Hut78 cells were analyzed by microarray expression and the results were validated by reverse transcription‑quantitative polymerase chain reaction, western blotting and knockout of signal transducer and activator of transcription 1 (STAT1). The results of the present study demonstrated that ribavirin suppressed the growth and clonogenicity of cells in a dose‑dependent manner. Ribavirin did not affect the expression of EZH2 nor altered its activity as evaluated by H3K27 trimethylation status. Furthermore, the results of transcriptome analysis indicated that the majority of the canonical pathways affected by ribavirin were associated with the immune system, including ‘antigen presentation’, ‘communication between innate and adaptive immune cells’ and ‘cross‑talk between dendritic and natural killer cells’. The results of gene expression analysis were confirmed, by demonstrating at the RNA and protein levels, downregulation of stearoyl‑CoA desaturase and upregulation of STAT1. Depletion of STAT1, which was proposed as a key regulator of the aforementioned pathways, exerted growth inhibitory effects almost to the same extent as ribavirin. In conclusion, ribavirin was proposed to exert growth inhibitory effects on lymphoma cell lines, particularly Hut78 cells, a cutaneous T‑cell lymphoma cell line. Of note, these effects may depend on, at least in part, the activation of canonical immune pathways regulated by the key factors STAT1 and interferon‑γ. Our results provide insight into the anti‑lymphoma potential of ribavirin; however, further investigations in preclinical and clinical studies are required to determine the effectiveness of ribavirin as a therapeutic agent for treating lymphoma.

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1	Sidwell RW, Robins RK and Hillyard IW: Ribavirin: An antiviral agent. Pharmacol Ther. 6:123–416. 1979. View Article : Google Scholar : PubMed/NCBI
2	Shepherd J, Jones J, Hartwell D, Davidson P, Price A and Waugh N: Interferon alpha (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: A systematic review and economic evaluation. Health Technol Assess. 111–205. (iii)2007.PubMed/NCBI
3	De la Cruz-Hernandez E, Medina-Franco JL, Trujillo J, Chavez-Blanco A, Dominguez-Gomez G, Perez-Cardenas E, Gonzalez-Fierro A, Taja-Chayeb L and Dueñas-Gonzalez A: Ribavirin as a tri-targeted antitumor repositioned drug. Oncol Rep. 33:2384–2392. 2015. View Article : Google Scholar : PubMed/NCBI
4	Assouline S, Culjkovic B, Cocolakis E, Rousseau C, Beslu N, Amri A, Caplan S, Leber B, Roy DC, Miller WH Jr and Borden KL: Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): A proof-of-principle clinical trial with ribavirin. Blood. 114:257–260. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kentsis A, Topisirovic I, Culjkovic B, Shao L and Borden KL: Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA. 101:18105–18110. 2004. View Article : Google Scholar : PubMed/NCBI
6	Borroto-Esoda K, Myrick F, Feng J, Jeffrey J and Furman P: In vitro combination of amdoxovir and the inosine monophosphate dehydrogenase inhibitors mycophenolic acid and ribavirin demonstrates potent activity against wild-type and drug-resistant variants of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 48:4387–4394. 2004. View Article : Google Scholar : PubMed/NCBI
7	Casaos J, Huq S, Lott T, Felder R, Choi J, Gorelick N, Peters M, Xia Y, Maxwell R, Zhao T, et al: Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors. Oncotarget. 9:8054–8067. 2018. View Article : Google Scholar : PubMed/NCBI
8	Volpin F, Casaos J, Sesen J, Mangraviti A, Choi J, Gorelick N, Frikeche J, Lott T, Felder R, Scotland SJ, et al: Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic. Oncogene. 36:3037–3047. 2007. View Article : Google Scholar
9	Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN, Wang L, Wang L, et al: EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 23:677–692. 2013. View Article : Google Scholar : PubMed/NCBI
10	Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, et al: Overexpression of Enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy. Haematologica. 96:712–719. 2011. View Article : Google Scholar : PubMed/NCBI
11	Soumyanarayanan U and Dymock BW: Recently discovered EZH2 and EHMT2 (G9a) inhibitors. Future Med Chem. 8:1635–1654. 2016. View Article : Google Scholar : PubMed/NCBI
12	Peveling-Oberhag J, Arcaini L, Bankov K, Zeuzem S and Herrmann E: The anti-lymphoma activity of antiviral therapy in HCV-associated B-cell non-Hodgkin lymphomas: A meta-analysis. J Viral Hepat. 23:536–544. 2016. View Article : Google Scholar : PubMed/NCBI
13	Pettersson F, Yau C, Dobocan MC, Culjkovic-Kraljacic B, Retrouvey H, Puckett R, Flores LM, Krop IE, Rousseau C, Cocolakis E, et al: Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B-type breast cancer. Clin Cancer Res. 17:2874–2884. 2011. View Article : Google Scholar : PubMed/NCBI
14	Pettersson F, Del Rincon SV, Emond A, Huor B, Ngan E, Ng J, Dobocan MC, Siegel PM and Miller WH Jr: Genetic and pharmacologic inhibition of eIF4E reduces breast cancer cell migration, invasion, and metastasis. Cancer Res. 75:1102–1112. 2015. View Article : Google Scholar : PubMed/NCBI
15	Sharma S, Baksi R and Agarwal M: Repositioning of anti-viral drugs as therapy for cervical cancer. Pharmacol Rep. 68:983–989. 2016. View Article : Google Scholar : PubMed/NCBI
16	Xi C, Wang L, Yu J, Ye H, Cao L and Gong Z: Inhibition of eukaryotic translation initiation factor 4E is effective against chemo-resistance in colon and cervical cancer. Biochem Biophys Res Commun. 503:2286–2292. 2018. View Article : Google Scholar : PubMed/NCBI
17	Richard SM and Martinez Marignac VL: Sensitization to oxaliplatin in HCT116 and HT29 cell lines by metformin and ribavirin and differences in response to mitochondrial glutaminase inhibition. J Cancer Res Ther. 11:336–340. 2015. View Article : Google Scholar : PubMed/NCBI
18	Kosaka T, Nagamatsu G, Saito S, Oya M, Suda T and Horimoto K: Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming. Cancer Sci. 104:1017–1026. 2013. View Article : Google Scholar : PubMed/NCBI
19	Culjkovic B and Borden KL: Understanding and targeting the eukaryotic translation initiation factor eIF4E in head and neck cancer. J Oncol 2009. 9816792009.
20	Attar-Schneider O, Drucker L and Gottfried M: Migration and epithelial-to-mesenchymal transition of lung cancer can be targeted via translation initiation factors eIF4E and eIF4GI. Lab Invest. 96:1004–115. 2016. View Article : Google Scholar : PubMed/NCBI
21	Tan K, Culjkovic B, Amri A and Borden KL: Ribavirin targets eIF4E dependent Akt survival signaling. Biochem Biophys Res Commun. 375:341–345. 2008. View Article : Google Scholar : PubMed/NCBI
22	Volpon L, Osborne MJ, Zahreddine H, Romeo AA and Borden KL: Conformational changes induced in the eukaryotic translation initiation factor eIF4E by a clinically relevant inhibitor, ribavirin triphosphate. Biochem Biophys Res Commun. 434:614–619. 2013. View Article : Google Scholar : PubMed/NCBI
23	Borden KL and Culjkovic-Kraljacic B: Ribavirin as an anti-cancer therapy: Acute myeloid leukemia and beyond? Leuk Lymphoma. 51:1805–1815. 2010. View Article : Google Scholar : PubMed/NCBI
24	Culjkovic-Kraljacic B, Fernando TM, Marullo R, Calvo-Vidal N, Verma A, Yang S, Tabbò F, Gaudiano M, Zahreddine H, Goldstein RL, et al: Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood. 127:858–868. 2016. View Article : Google Scholar : PubMed/NCBI
25	Rutherford SC, Stewart EN, Chen Z, Chadburn A, Wehrli NE, van Besien K, Martin P, Furman RR, Leonard JP and Cerchietti L: The eIF4E inhibitor ribavirin as a potential antilymphoma therapeutic: Early clinical data. Leuk Lymphoma. 59:256–258. 2018. View Article : Google Scholar : PubMed/NCBI
26	Dunn GP, Koebel CM and Schreiber RD: Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 6:836–848. 2006. View Article : Google Scholar : PubMed/NCBI
27	Ferrantini M, Capone I and Belardelli F: Interferon-alpha and cancer: Mechanisms of action and new perspectives of clinical use. Biochimie. 89:884–893. 2007. View Article : Google Scholar : PubMed/NCBI
28	Belardelli F, Ferrantini M, Proietti E and Kirkwood JM: Interferon-alpha in tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 13:119–134. 2002. View Article : Google Scholar : PubMed/NCBI
29	Rotman Y, Noureddin M, Feld JJ, Guedj J, Witthaus M, Han H, Park YJ, Park SH, Heller T, Ghany MG, et al: Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C. Gut. 63:161–169. 2014. View Article : Google Scholar : PubMed/NCBI
30	Sun WH, Pabon C, Alsayed Y, Huang PP, Jandeska S, Uddin S, Platanias LC and Rosen ST: Interferon-alpha resistance in a cutaneous T-cell lymphoma cell line is associated with lack of STAT1 expression. Blood. 91:570–576. 1998.PubMed/NCBI
31	Sugaya M, Tokura Y, Hamada T, Tsuboi R, Moroi Y, Nakahara T, Amano M, Ishida S, Watanabe D, Tani M, et al: Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides. J Dermatol. 41:50–56. 2014. View Article : Google Scholar : PubMed/NCBI
32	Kyvernitakis A, Duvic M, Mahale P and Torres HA: Interferon-based treatment for patients with mycosis fungoides and hepatitis C virus infection: A case series. Am J Clin Dermatol. 15:451–456. 2014. View Article : Google Scholar : PubMed/NCBI
33	Care MA, Westhead DR and Tooze RM: Gene expression meta-analysis reveals immune response convergence on the IFNγ-STAT1-IRF1 axis and adaptive immune resistance mechanisms in lymphoma. Genome Med. 7:962015. View Article : Google Scholar : PubMed/NCBI
34	Woo J, Kim HY, Byun BJ, Chae CH, Lee JY, Ryu SY, Park WK, Cho H and Choi G: Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors. Bioorg Med Chem Lett. 24:2486–2492. 2014. View Article : Google Scholar : PubMed/NCBI