Abstract
Vesicular stomatitis virus has been known as a potent antitumor agent because of its selective replication and lysis of tumor cells and immune-stimulating properties. In response to cellular stress and enhanced metabolism, tumor cells activate autophagy, to provide energy for the cells and preventing tumor destruction. Inhibition of autophagy can increase the therapeutic potential of many antitumor methods. This study aimed to check the efficacy of combined VSV and three-methyl adenine (3-MA) in treating a tumor model in mice. TC-1, a line of C57BL/6 mouse lung cells transformed by HPV-16 E7 and E6 oncoproteins, as well as human Ras, were used for experiments. The viability after treatment with the optimized concentration of 3MA with or without combination with VSV was assessed by MTT. C57BL/6 male mice were injected with TC-1, and after tumor formation, 3-MA and VSV alone or in combination in two different protocols were injected into tumor mice. Tumor size, tumor-specific CTL response, and apoptosis rate were evaluated. The results showed that 3-MA combined with VSV causes more lethality in tumor cells in vitro. In vivo studies also showed that combined VSV and 3-MA treatment inhibits the progression of TC-1 cancer cells with higher efficiency, especially in daily 3-MA treatment along with four doses of VSV injection with four days’ intervals. In addition, the rate of apoptosis and cytotoxic T cells activity in the groups injected with 3-MA and the virus were higher than groups receiving each agent alone. In conclusion, the association of VSV with 3-MA increases its oncolysis activity and subsequently more stimulates the immune system against the tumor. This finding suggests a combinational approach for tumor therapy with therapy. Combining oncolytic VSV with 3-MA as an autophagy inhibitor agent can improve the efficacy of tumor treatment. This combination therapy approach enhances apoptosis in tumors as well as T cell cytotoxicity against tumor cells.
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REFERENCES
Sridhar S., Botbol Y., Macian F., Cuervo A.M. 2012. Autophagy and disease: Always two sides to a problem. J. Pathol. 226 (2), 255–273. https://doi.org/10.1002/path.3025
Kundu M., Thompson C.B. 2005. Macroautophagy versus mitochondrial autophagy: a question of fate? Cell Death Differ. 12 (Suppl. 2), 1484–1489. https://doi.org/10.1038/sj.cdd.4401780
Fulda S. 2018. Targeting autophagy for the treatment of cancer. Biol. Chem. 399 (7), 673–677. https://doi.org/10.1515/hsz-2018-0105
Linder B., Kögel D. 2019. Autophagy in cancer cell death. Biology (Basel). 8 (4), 82. https://doi.org/10.3390/biology8040082
Yun C.W., Lee S.H. 2018. The roles of autophagy in cancer. Int. J. Mol. Sci. 19 (11), 3466. https://doi.org/10.3390/ijms19113466
Pérez-Hernández M., Arias A., Martínez-García D., Pérez-Tomás R., Quesada R., Soto-Cerrato V. 2019. Targeting autophagy for cancer treatment and tumor chemosensitization. Cancers (Basel). 11 (10), 1599. https://doi.org/10.3390/cancers11101599
Bishnoi S., Tiwari R., Gupta S., Byrareddy S.N., Nayak D. 2018. Oncotargeting by Vesicular Stomatitis Virus (VSV): Advances in cancer therapy. Viruses. 10 (2), 90. https://doi.org/10.3390/v10020090
Saito K., Shirasawa H., Isegawa N., Shiiba M., Uzawa K., Tanzawa H. 2009. Oncolytic virotherapy for oral squamous cell carcinoma using replication-competent viruses. Oral. Oncol. 45 (12), 1021–1027. https://doi.org/10.1016/j.oraloncology.2009.09.002
Boisgerault N., Tangy F., Gregoire M. 2010. New perspectives in cancer virotherapy: Bringing the immune system into play. Immunotherapy. 2 (2), 185–199. https://doi.org/10.2217/imt.10.6
Malilas W., Koh S.S., Lee S., Srisuttee R., Cho I.-R., Moon J., Kaowinn S., Johnston R.N., Chung Y.-H. 2014. Suppression of autophagic genes sensitizes CUG2-overexpressing A549 human lung cancer cells to oncolytic vesicular stomatitis virus-induced apoptosis. Int. J. Oncol. 44 (4), 1177–1184. https://doi.org/10.3892/ijo.2014.2264
Alain T., Lun X., Martineau Y., Sean P., Pulendran B., Petroulakis E., Zemp F.J., Lemay C.G., Roy D., Bell J.C., Thomas G., Kozma S.C., Forsyth P.A., Costa-Mattioli M., Sonenberg N. 2010. Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production. Proc. Natl. Acad. Sci. U. S. A. 107 (4), 1576–1581.https://doi.org/10.1073/pnas.0912344107
Shulak L., Beljanski V., Chiang C., Dutta S.M., Van Grevenynghe J., Belgnaoui S.M., Nguyên T.L.-A., Di Lenardo T., Semmes O.J., Lin R., Hiscott J. 2014. Histone deacetylase inhibitors potentiate vesicular stomatitis virus oncolysis in prostate cancer cells by modulating NF-κB-dependent autophagy. J. Virol. 88 (5), 2927–2940. https://doi.org/10.1128/JVI.03406-13
Breitbach C.J., De Silva N.S., Falls T.J., Aladl U., Evgin L., Paterson J., Sun Y.Y., Roy D.G., Rintoul J.L., Daneshmand M., Parato K., Stanford M.M., Lichty B.D., Fenster A., Kirn D., et al. 2011. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19 (5), 886–894. https://doi.org/10.1038/mt.2011.26
Tan S., Peng X., Peng W., Zhao Y., Wei Y. 2015. Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer. Oncol. Lett. 9 (5), 2056–2062. https://doi.org/10.3892/ol.2015.2996
Onorati A.V., Dyczynski M., Ojha R., Amaravadi R.K. 2018. Targeting autophagy in cancer. Cancer. 124 (16), 3307–3318. https://doi.org/10.1002/cncr.31335
Yang Z.J., Chee C.E., Huang S., Sinicrope F.A. 2011. The role of autophagy in cancer: Therapeutic implications. Mol. Cancer Ther. 10 (9), 1533–1541. https://doi.org/10.1158/1535-7163.MCT-11-0047
Kuo C.J., Hansen M., Troemel E. 2018. Autophagy and innate immunity: insights from invertebrate model organisms. Autophagy. 14 (2), 233–242. https://doi.org/10.1080/15548627.2017.1389824
Hu L., Jiang K., Ding C., Meng S. 2017. Targeting autophagy for oncolytic immunotherapy. Biomedicines. 5 (1), 5. https://doi.org/10.3390/biomedicines5010005
Rodriguez-Rocha H., Gomez-Gutierrez J.G., Garcia-Garcia A., Rao X.-M., Chen L., McMasters K.M., Zhou H.S. 2011. Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology. 416 (1–2), 9–15. https://doi.org/10.1016/j.virol.2011.04.017
Talebi M., Bamdad T., Arefian E., Ahmadi H., Karimi H., Choobin H. 2016. Autophagy knock down: as a booster for the replication of viruses in cell culture. Arch. Med. Lab. Sci. 2 (2), 62–66.
Nabizadeh A., Bamdad T., Arefian E., Razavi Nikoo S.H. 2016. Autophagy gene activity may act as a key factor for sensitivity of tumor cells to oncolytic vesicular stomatitis virus. Iran J. Cancer Prev. 9 (1), e3919. https://doi.org/10.17795/ijcp-3919
Jiang K., Li Y., Zhu Q., Xu J., Wang Y., Deng W., Liu Q., Zhang G., Meng S. 2014. Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells. BMC Cancer. 14, 551. https://doi.org/10.1186/1471-2407-14-551
Botta G., Passaro C., Libertini S., Abagnale A., Barbato S., Maione A.S., Hallden G., Beguinot F., Formisano P., Portella G. 2012. Inhibition of autophagy enhances the effects of E1A-defective oncolytic adenovirus dl922-947 against glioma cells in vitro and in vivo. Hum. Gene Ther. 23 (6), 623–634. https://doi.org/10.1089/hum.2011.120
Baird S.K., Aerts J.L., Eddaoudi A., Lockley M., Le-moine N.R., McNeish I.A. 2008. Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer. Oncogene. 27 (22), 3081–3090. https://doi.org/10.1038/sj.onc.1210977
Colunga A.G., Laing J.M., Aurelian L. 2010. The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins. Gene Ther. 17 (3), 315–327. https://doi.org/10.1038/gt.2009.126
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This work was supported by the Faculty of Medical Sciences, Tarbiat Modares University (funding no. TMU-MED. 9327).
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Zadaloo, K.M., Bamdad, T., Abdoli, A. et al. Inhibition of Autophagy by 3-MA Increases Oncolysis Effect of VSV in a Murine Model of Cancer. Mol Biol 56, 283–289 (2022). https://doi.org/10.1134/S0026893322020169
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DOI: https://doi.org/10.1134/S0026893322020169