PI3K inhibitor ZSTK474 enhancing the antitumor of vesicular stomatitis virus Δ51 against osteosarcoma

doi:10.16098/j.issn.0529-1356.2022.04.013

Abstract

Abstract:

Objective To explore whether PI3K inhibitor combined with oncolytic virus can play an effective oncolytic effect on osteosarcoma. Methods The cytotoxicity to tumor cells was detected by MTT method, and the mechanism of enhancing the anti-tumor activity was explored by observation of the swelling of endoplasmic reticulum using electron microscope and the expression of apoptosis-related proteins using Western blotting. The tumor clearance ability of the combination of the PI3k inhibitor ZSTK474 and vesicular stomatitis virus Δ51 (VSVΔ51) was verified by anti-tumor experiment in vivo. The apoptosis of tumor cells was verified by immunohistochemistry. Results PI3K inhibitor could be used as sensitizers of oncolytic VSVΔ51, and confirmed that they promoted the strong apoptosis of osteosarcoma cells by aggravating the stress of endoplasmic reticulum in tumor cells (P＜0.01). In vivo experiments also showed that PI3K inhibitors combined with VSVΔ51 could significantly promote the oncolytic effect of osteosarcoma (P＜0.001), and this combination therapy enhanced the infiltration of immune cells in the tumor (P＜0.001). Conclusion PI3K inhibitors combined with oncolytic virus is a potential therapy for osteosarcoma.

Key words: Osteosarcoma, Oncolytic virus, Vesicular stomatitis virus Δ51, Phosphatidylinositol 3-kinase inhibitor, Western blotting, Mouse

CLC Number:

R730.5

LIU Li-zhu LI Chao-yi LIN Shi-wei QU Ye TANG Qiang . PI3K inhibitor ZSTK474 enhancing the antitumor of vesicular stomatitis virus Δ51 against osteosarcoma[J]. Acta Anatomica Sinica, 2022, 53(4): 498-506.

References

［1］Song K, Song J, Lin K，et al.Survival analysis of patients with metastatic osteosarcoma: a surveillance, epidemiology, and end results population-based study ［J］. Int Orthop, 2019, 43 (8):1983-1991.

［2］Brady SW, Ma X, Bahrami A, et al.The clonal evolution of metastatic osteosarcoma as shaped by cisplatin treatment ［J］. Mol Cancer Res, 2019, 17 (4):895-906.

［3］Zou P, Tang R, Luo M.Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: a systematic review and meta-analysis ［J］. Int Immunopharmacol, 2019, 78:106050.

［4］Coffin R.Interview with robert coffin, inventor of t-vec: the first oncolytic immunotherapy approved for the treatment of cancer ［J］. Immunotherapy, 2016, 8 (2):103-106.

［5］Kimpel J, Urbiola C, Koske I, et al.The oncolytic virus vsv-gp is effective against malignant melanoma ［J］. Viruses, 2018, 10 (3):108.

［6］Stojdl DF, Lichty BD, tenOever BR, et al.Vsv strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents ［J］. Cancer Cell, 2003, 4 (4):263-275.

［7］Malinzi J, Ouifki R, Eladdadi A, et al.Enhancement of chemotherapy using oncolytic virotherapy: mathematical and optimal control analysis ［J］. Math Biosci Eng, 2018, 15 (6):1435-1463.

［8］Rahmani F, Ziaeemehr A, Shahidsales S, et al.Role of regulatory mirnas of the pi3k/akt/mtor signaling in the pathogenesis of hepatocellular carcinoma ［J］. J Cell Physiol, 2020, 235(5):4146-4152.

［9］Kanaizumi H, Higashi C, Tanaka Y, et al.PI3K/Akt/mTOR signalling pathway activation in patients with er-positive, metachronous, contralateral breast cancer treated with hormone therapy ［J］. Oncol Lett, 2019, 17 (2):1962-1968.

［10］Mahoney DJ, Lefebvre C, Allan K, et al.Virus-tumor interactome screen reveals er stress response can reprogram resistant cancers for oncolytic virus-triggered caspase-2 cell death ［J］. Cancer Cell, 2011, 20 (4):443-456.

［11］Ben Yebdri F, Van Grevenynghe J, Tang VA, et al.Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis ［J］. Mol Ther, 2013, 21 (11):2043-2053.

［12］Kiyuna T, Tome Y, Miyake K, et al.Eribulin suppressed cisplatinum- and doxorubicin-resistant recurrent lung metastatic osteosarcoma in a patient-derived orthotopic xenograft mouse model ［J］. Anticancer Res, 2019, 39 (9):4775-4779.

［13］Blake Z, Marks DK, Gartrell RD, et al.Complete intracranial response to talimogene laherparepvec (t-vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition ［J］. J Immunother Cancer, 2018, 6 (1):25.

［14］Bommareddy PK, Patel A, Hossain S, et al.Talimogene laherparepvec (t-vec) and other oncolytic viruses for the treatment of melanoma ［J］. Am J Clin Dermatol, 2017, 18 (1):1-15.

［15］Harrington KJ, Puzanov I, Hecht JR, et al.Clinical development of talimogene laherparepvec (t-vec): a modified herpes simplex virus type-1-derived oncolytic immunotherapy ［J］. Expert Rev Anticancer Ther, 2015, 15 (12):1389-1403.

［16］Denton NL, Chen CY, Hutzen B, et al.Myelolytic treatments enhance oncolytic herpes virotherapy in models of ewing sarcoma by modulating the immune microenvironment ［J］. Mol Ther Oncolytics, 2018, 11:62-74. 

［17］SM OB, Mathis JM.Oncolytic virotherapy for breast cancer treatment ［J］. Curr Gene Ther, 2018, 18 (4):192-205.

［18］Larabi A, Barnich N, Nguyen HTT.New insights into the interplay between autophagy, gut microbiota and inflammatory responses in ibd ［J］. Autophagy, 2020,16(1):38-51.

［19］Stepanenko AA, Chekhonin VP. Recent advances in oncolytic virotherapy and immunotherapy for glioblastoma: a glimmer of hope in the search for an effective therapy ［J］ ? Cancers (Basel), 2018, 10 (12):492.

［20］Yuan P, Dong L, Cheng Q, et al.Prototype foamy virus elicits complete autophagy involving the er stress-related upr pathway ［J］. Retrovirology, 2017, 14 (1):16.

［21］Namatame N, Tamaki N, Yoshizawa Y, et al.Antitumor profile of the pi3k inhibitor zstk474 in human sarcoma cell lines ［J］. Oncotarget, 2018, 9 (80):35141-35161.

［22］Killock D.Skin cancer: T-vec oncolytic viral therapy shows promise in melanoma ［J］. Nat Rev Clin Oncol, 2015, 12 (8):438.

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