Oncolytic viral therapy for neuroblastoma cells with Sindbis virus AR339 strain

Takenouchi, Ayako; Saito, Kengo; Saito, Eizo; Saito, Takeshi; Hishiki, Tomoro; Matsunaga, Tadashi; Isegawa, Naohisa; Yoshida, Hideo; Ohnuma, Naomi; Shirasawa, Hiroshi

doi:10.1007/s00383-015-3784-y

Cited by 10 publications

(8 citation statements)

References 63 publications

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“…SINV infects neurons and induces apoptosis, showing cytotoxicity toward human neuroblastoma cells [8,9]. Previous studies have shown that SINV-induced apoptosis is most efficiently triggered in the presence of structural proteins [16,22], and transient overexpression of SINV structural proteins or UV-inactivated SINV can induce apoptosis in Chinese hamster ovary (CHO) cells and N18 mouse neuroblastoma cells [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…SINV induces apoptosis in most vertebrate cell lines and can be blocked in cells where anti-apoptotic Bcl-2 is expressed [12]. Our previous reports have suggested that human NB cells highly expressing Bcl-2 are resistant to SINV-induced cytotoxicity [7,9]. Thus, cell death signals may be blocked by multiple mechanisms in NB cells, which may, at least partially, compensate for each other.…”

Section: Discussionmentioning

confidence: 99%

“…xenograft tumors are also susceptible to replication-competent SINV [9]. SINV, a mosquito-borne alphavirus, is an enveloped, plus-strand RNA virus that causes infection of neurons and age-dependent encephalomyelitis in mice, and mild mosquito-borne viral arthritis in humans [10].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have reported that the SINV AR339 strain may be used as a novel therapeutic agent for human cervical, ovarian, and oral cancer [ 6 – 8 ]. Human NB cells and NB xenograft tumors are also susceptible to replication-competent SINV [ 9 ]. SINV, a mosquito-borne alphavirus, is an enveloped, plus-strand RNA virus that causes infection of neurons and age-dependent encephalomyelitis in mice, and mild mosquito-borne viral arthritis in humans [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Sindbis viral structural protein cytotoxicity on human neuroblastoma cells

Saito

Hishiki

et al. 2020

Pediatr Surg Int

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Purpose Oncolytic viral therapy for neuroblastoma (NB) cells with Sindbis virus (SINV) is a promising strategy for treating high-risk NB. Here, we evaluated the possibility of using SINV structural proteins as therapeutic agents for NB since UV-inactivated SINV could induce cytopathogenic effects. Methods The cytotoxicity of UV-inactivated SINV toward human NB cell lines NB69, NGP, GOTO, NLF, SK-N-SH, SH-SY5Y, CHP134, NB-1, IMR32, and RT-BM-1 were analyzed. Apoptosis was confirmed by TUNEL assays. To determine the components of SINV responsible for the cytotoxicity of UV-inactivated SINV, expression vectors encoding the structural proteins, namely capsid, E2, and E1, were transfected in NB cells. Cytotoxicity was evaluated by MTT assays. Results UV-inactivated SINV elicited more significant cytotoxicity in NB69, NGP, and RT-BM-1 than in normal human fibroblasts. Results of the transfection experiments showed that all NB cell lines susceptible to UV-inactivated SINV were highly susceptible to the E1 protein, whereas fibroblasts transfected with vectors harboring capsid, E1, or E2 were not. Conclusions We demonstrated that the cytotoxicity of the UV-inactivated SINV is due to apoptosis induced by the E1 structural protein of SINV, which can be used selectively as a therapeutic agent for NB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sindbis viral structural protein cytotoxicity on human neuroblastoma cells

Saito

Hishiki

et al. 2020

Pediatr Surg Int

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“…This suggests that naturally occurring oncolytic SIN vectors can be attractive for cancer therapy [67]. Moreover, the oncolytic SINV AR339 strain was evaluated for cytotoxicity and viral growth in five human neuroblastoma cell lines (SK-N-SH, IMR-32, LAN-5, GOTO and RT-BM-1) and in vivo in nude mice implanted with neuroblastoma xenografts [68]. SIN AR339 induced significant cytotoxicity and mRNA levels of the anti-apoptotic genes Bcl-2 and Bcl-xL were increased in LAN-5 and RT-BM-1 cells.…”

Section: Oncolytic Alphavirus Approachesmentioning

confidence: 99%

Oncolytic Alphaviruses in Cancer Immunotherapy

Lundström¹

2017

Vaccines

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Oncolytic viruses show specific targeting and killing of tumor cells and therefore provide attractive assets for cancer immunotherapy. In parallel to oncolytic viral vectors based on adenoviruses and herpes simplex viruses, oncolytic RNA viruses and particularly alphaviruses have been evaluated as delivery vehicles. Immunization studies in experimental rodent models for various cancers including glioblastoma, hematologic, hepatocellular, colon, cervix, and lung cancer as well as melanoma have been conducted with naturally occurring oncolytic alphavirus strains such as M1 and Sindbis AR339. Moreover, animals were vaccinated with engineered oncolytic replication-deficient and -competent Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus vectors expressing various antigens. Vaccinations elicited strong antibody responses and resulted in tumor growth inhibition, tumor regression and even complete tumor eradication. Vaccination also led to prolonged survival in several animal models. Furthermore, preclinical evaluation demonstrated both prophylactic and therapeutic efficacy of oncolytic alphavirus administration. Clinical trials in humans have mainly been limited to safety studies so far.

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