Antitumor effects of ribavirin in combination with TMZ and IFN‑&beta; in malignant glioma cells

Ochiai,Yushi; Sumi,Koichiro; Sano,Emiko; Yoshimura,Sodai; Yamamuro,Shun; Ogino,Akiyoshi; Ueda,Takuya; Suzuki,Yutaka; Nakayama,Tomohiro; Hara,Hiroyuki; Katayama,Yoichi; Yoshino,Atsuo

doi:10.3892/ol.2020.12039

Antitumor effects of ribavirin in combination with TMZ and IFN‑β in malignant glioma cells

Authors:
- Yushi Ochiai
- Koichiro Sumi
- Emiko Sano
- Sodai Yoshimura
- Shun Yamamuro
- Akiyoshi Ogino
- Takuya Ueda
- Yutaka Suzuki
- Tomohiro Nakayama
- Hiroyuki Hara
- Yoichi Katayama
- Atsuo Yoshino
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Affiliations: Department of Neurological Surgery, Nihon University School of Medicine, Tokyo 173‑8610, Japan, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277‑8562, Japan, Division of Companion Diagnostics, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 173‑8610, Japan, Division of Functional Morphology, Department of Functional Morphology, Nihon University School of Medicine, Tokyo 173‑8610, Japan
Published online on: August 31, 2020 https://doi.org/10.3892/ol.2020.12039
Article Number: 178
Copyright: © Ochiai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The prognosis of gioblastoma, the standard chemotherapy agent for which is temozolomide (TMZ), remains poor despite recent advances in multimodal treatments. Therefore, it is necessary to identify and develop novel therapeutics for this malignant disease. Ribavirin, an anti‑viral agent which is one of the standard agents for treatment of chronic hepatitis C in combination with interferon (IFN), was recently revealed to have an antitumor potential towards various tumor cells, including malignant glioma cells. The aim of the present study was to examine the antitumor effect of ribavirin in combination with TMZ and IFN‑β on glioma cells and to evaluate the possibility that such combinations might represent a novel candidate for glioblastoma therapy. The combination of ribavirin with TMZ and IFN‑β displayed a significant cell growth inhibitory effect with a ribavirin dose‑dependency, including a relatively low concentration of ribavirin, on not only TMZ‑sensitive but also TMZ‑resistant malignant glioma cells. The antitumor efficacy of such a combination further indicated a synergistic interaction when assessed by the Chou‑Talalay method. Furthermore, flow cytometry analysis suggested that apoptosis induction was one of the possible biological processes underlying the synergistic antitumor effect of these triple combination treatments. Therefore, such combinations may be potentially important in the clinical setting for glioblastoma treatment, although further detailed studies, e.g. on the adverse effects, are required.

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1	Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI
2	Sidwell RW, Huffman JH, Khare GP, Allem LB, Witkowski JT and Robins RK: Broad-spectrum antiviral activity of Virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 177:705–706. 1972. View Article : Google Scholar : PubMed/NCBI
3	Kohli A, Shaffer A, Sherman A and Kottilil S: Treatment of hepatitis C: A systematic review. JAMA. 312:631–640. 2014. View Article : Google Scholar : PubMed/NCBI
4	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
5	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
6	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
7	Ogino A, Sano E, Ochiai Y, Yamamuro S, Tashiro S, Yachi K, Ohta T, Fukushima T, Okamoto Y, Tsumoto K, et al: Efficacy of ribavirin against malignant glioma cell lines. Oncol Lett. 8:2469–2474. 2014. View Article : Google Scholar : PubMed/NCBI
8	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
9	Volpin F, Casaos J, Sesen J, Mangraviti A, Choi J, Gorelick N, Frieche 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. 2017. View Article : Google Scholar : PubMed/NCBI
10	Ochiai Y, Sano E, Okamoto Y, Yoshimura S, Makita K, Yamamuro S, Ohta T, Ogino A, Tadakuma H, Ueda T, et al: Efficacy of ribavirin against malignant glioma cell lines: Follow-up study. Oncol Rep. 39:537–544. 2018.PubMed/NCBI
11	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
12	Saito R, Mizuno M, Hatano M, Kumabe T, Yoshimoto T and Yoshida J: Two different mechanisms of apoptosis resistance observed in interferon-β induced apoptosis of human glioma cells. J Neurooncol. 67:273–280. 2004. View Article : Google Scholar : PubMed/NCBI
13	Yoshino A, Katayama Y, Yokoyama T, Watanabe T, Ogino A, Ota T, Komine C, Fukushima T and Kusama K: Therapeutic implication of interferon regulatory factor 1 (IRF-1) and IRF-2 in diffusely infiltrating astrocytomas (DIA): Response to (IFN)-beta in glioblastoma cells and prognostic value for DIA. J Neurooncol. 74:249–260. 2005. View Article : Google Scholar : PubMed/NCBI
14	Vannucchi S, Chiantore MV, Mangino G, Percario ZA, Affabris E, Fiorucci G and Romeo G: Perspective in biomolecular therapeutic intervention in cancer: From the early to the new strategies with type 1 interferons. Curr Med Chem. 14:667–679. 2007. View Article : Google Scholar : PubMed/NCBI
15	Yoshino A, Tashiro S, Ogino A, Yachi K, Ohta T, Fukushima T, Watanabe T, Katayama Y, Okamoto Y, Sano E and Tsumoto K: Gene expression profiles predicting the response to IFN-β and a combination of temozolomide and IFN-β in malignant gliomas. Int J Oncol. 39:529–542. 2011.PubMed/NCBI
16	Yoshida J, Kajita Y, Wakabayashi T and Sugita K: Long-term follow-up results of 175 patients with malignant glioma: Importance of radical tumor resection and post-operative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir. 127:55–59. 1994. View Article : Google Scholar : PubMed/NCBI
17	Natsume A, Ishii D, Wakabayashi T, Tsuno T, Hatano H, Mizuno M and Yoshida J: IFN-beta down-regulates the expression of DNA repair gene MGMT and sensitizes resistant glioma cells to temozolomide. Cancer Res. 65:7573–7579. 2005. View Article : Google Scholar : PubMed/NCBI
18	Park JA, Joe YA, Kim TG and Hong YK: Potentiation of anti-glioma effect with combined temozolomide and interferon-beta. Oncol Rep. 16:1253–1260. 2006.PubMed/NCBI
19	Yoshino A, Ogino A, Yachi K, Ohta T, Fukushima T, Watanabe T, Katayama Y, Okamoto Y, Naruse N and Sano E: Effect of IFN-beta on human glioma cell lines with temozolomide resistance. Int J Oncol. 35:139–148. 2009. View Article : Google Scholar : PubMed/NCBI
20	Schlosser SF, Schuler M, Berg CP, Lauber K, Schulze-Osthoff K, Schmahl FW and Wesselborg S: Ribavirin and alpha interferon enhance death receptor-mediated apoptosis and caspase activation in human hepatoma cells. Antimicrob Agents Chemother. 47:1912–1921. 2003. View Article : Google Scholar : PubMed/NCBI
21	Teng L, Ding D, Chen Y, Dai H, Liu G, Qiao Z and An R: Anti-tumor effect of ribavirin in combination with interferon-α on renal cell carcinoma cell lines in vitro. Cancer Cell Int. 14:632014. View Article : Google Scholar : PubMed/NCBI
22	Yoshino A, Ogino A, Yachi K, Ohta T, Fukushima T, Watanabe T, Katayama Y, Okamoto Y, Naruse N, Sano E and Tsumoto K: Gene expression profiling predicts response to temozolomide in malignant gliomas. Int J Oncol. 36:1367–1377. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wischhusen J, Naumann U, Ohgaki H, Rastinejad F and Weller M: CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene. 22:8233–8245. 2003. View Article : Google Scholar : PubMed/NCBI
24	Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA and Stupp R: Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 10:3728–3736. 2004. View Article : Google Scholar : PubMed/NCBI
25	Naik GS and Tyagi MG: A pharmacological profile of ribavirin and monitoring of its plasma concentration in chronic hepatitis C infection. J Clin Exp Hepatol. 2:42–54. 2012. View Article : Google Scholar : PubMed/NCBI
26	Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 58:621–681. 2006. View Article : Google Scholar : PubMed/NCBI
27	Ren H, Tan X, Dong Y, Giese A, Chou TC, Rainov N and Yang B: Differential effect of imatinib and synergism of combination treatment with chemotherapeutic agents in malignant glioma cells. Basic Clin Pharmacol Toxicol. 104:241–252. 2009. View Article : Google Scholar : PubMed/NCBI
28	Kast RE, Skuli N, Cos S, Karpel-Massler G, Shiozawa Y, Goshen R and Halatsch ME: The ABC7 regimen: A new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy. Breast Cancer. 9:495–514. 2017.PubMed/NCBI
29	Stewart WE, Gosser JB and Lockart RZ Jr: Priming: A nonantiviral function of interferon. J Virol. 7:792–801. 1971. View Article : Google Scholar : PubMed/NCBI