Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus

Felt, Sébastien A.; Moerdyk-Schauwecker, Megan; Grdzelishvili, Valery Z.

doi:10.1016/j.virol.2014.10.026

Cited by 33 publications

(23 citation statements)

References 62 publications

(139 reference statements)

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“…Recently, we showed that VSV-DM51 was able to induce apoptosis efficiently in 7 out of 10 tested human PDAC cell lines, and determined that the VSV-mediated apoptosis activation mechanism depends on both the VSV M protein and the PDAC cell line [86]. Three cell lines constitutively expressing high levels of ISGs were resistant to apoptosis under most experimental conditions, even when VSV replication levels were dramatically increased by Jak inhibitor I treatment [86]. We discuss different approaches to increase direct oncotoxicity of VSV-based OV therapy in more detail in the following section.…”

Section: Other Approaches To Improve Vsv Oncoselectivitymentioning

confidence: 99%

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

Felt

Grdzelishvili

2017

Journal of General Virology

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Oncolytic virus (OV) therapy is an anti-cancer approach that uses viruses that preferentially infect, replicate in and kill cancer cells. Vesicular stomatitis virus (VSV, a rhabdovirus) is an OV that is currently being tested in the USA in several phase I clinical trials against different malignancies. Several factors make VSV a promising OV: lack of pre-existing human immunity against VSV, a small and easy to manipulate genome, cytoplasmic replication without risk of host cell transformation, independence of cell cycle and rapid growth to high titres in a broad range of cell lines facilitating large-scale virus production. While significant advances have been made in VSV-based OV therapy, room for improvement remains. Here we review recent studies (published in the last 5 years) that address 'old' and 'new' challenges of VSV-based OV therapy. These studies focused on improving VSV safety, oncoselectivity and oncotoxicity; breaking resistance of some cancers to VSV; preventing premature clearance of VSV; and stimulating tumour-specific immunity. Many of these approaches were based on combining VSV with other therapeutics. This review also discusses another rhabdovirus closely related to VSV, Maraba virus, which is currently being tested in Canada in phase I/II clinical trials.

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Section: Other Approaches To Improve Vsv Oncoselectivitymentioning

confidence: 99%

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

Felt

Grdzelishvili

2017

Journal of General Virology

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“…The human PDAC cell line HPAF-II, which showed the highest level of resistance to VSV in our previous studies, was the main focus of this study (26)(27)(28)(29)(30). In addition, many experiments included Hs766T, another VSV-resistant human PDAC cell line, as well as two VSV-permissive human PDAC cell lines, MIA PaCa-2 and Suit2.…”

Section: Vsv Attachment To Hpaf-ii Cells Is Impairedmentioning

confidence: 99%

Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus

Felt

Droby

Grdzelishvili

2017

J Virol

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Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma cell (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of resistance are still unclear. JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor I) strongly stimulate VSV replication and oncolysis in all resistant cell lines but only partially improve the susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication rather than on receptor specificity, with several ubiquitously expressed cell surface molecules playing a role in VSV attachment to host cells. However, as VSV attachment to PDAC cells has never been tested before, here we examined if it was possibly inhibited in resistant PDAC cells. Our data show a dramatically weaker attachment of VSV to HPAF-II cells, the most resistant human PDAC cell line. Although sequence analysis of low-density lipoprotein (LDL) receptor (LDLR) mRNA did not reveal any amino acid substitutions in this cell line, HPAF-II cells displayed the lowest level of LDLR expression and dramatically lower LDL uptake. Treatment of cells with various statins strongly increased LDLR expression levels but did not improve VSV attachment or LDL uptake in HPAF-II cells. However, LDLR-independent attachment of VSV to HPAF-II cells was dramatically improved by treating cells with Polybrene or DEAE-dextran. Moreover, combining VSV with ruxolitinib and Polybrene or DEAE-dextran successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication.IMPORTANCE Oncolytic virus (OV) therapy is an anticancer approach that uses viruses that selectively infect and kill cancer cells. This study focuses on oncolytic vesicular stomatitis virus (VSV) against pancreatic ductal adenocarcinoma (PDAC) cells. Although VSV is effective against most PDAC cells, some are highly resistant to VSV, and the mechanisms are still unclear. Here we examined if VSV attachment to cells was inhibited in resistant PDAC cells. Our data show very inefficient attachment of VSV to the most resistant human PDAC cell line, HPAF-II. However, VSV attachment to HPAF-II cells was dramatically improved by treating cells with polycations. Moreover, combining VSV with polycations and ruxolitinib (which inhibits antiviral signaling) successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication. We envision that this novel triple-combination approach could be used in the future to treat PDAC tumors that are highly resistant to OV therapy.KEYWORDS DEAE-dextran, combination treatment, oncolytic virus, pancreatic cancer, Polybrene, polycation, resistance, vesicular stomatitis virus, virus attachment, type I interferon, ruxolitinib

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“…Particularly, VSV vectors have been subjected to aggressive pancreatic ductal adenocarcinoma (PDAC) showing superiority to Sendai virus and RSV in 13 clinically relevant human pancreatic cell lines, although the response varied from one cell line to another [85]. Moreover, evaluation in ten PDAC cell lines of three VSV vectors expressing the wild-type matrix protein or ∆M51 showed activation of VSV-mediated apoptosis [86]. However, high constitutive expression of IFN-stimulated genes (ISGs) was discovered in three cell lines, which also contributed to resistance to apoptosis.…”

Section: Self-replicating Rna Virus-based Vaccinesmentioning

confidence: 99%

Replicon RNA Viral Vectors as Vaccines

Lundström¹

2016

Vaccines

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Single-stranded RNA viruses of both positive and negative polarity have been used as vectors for vaccine development. In this context, alphaviruses, flaviviruses, measles virus and rhabdoviruses have been engineered for expression of surface protein genes and antigens. Administration of replicon RNA vectors has resulted in strong immune responses and generation of neutralizing antibodies in various animal models. Immunization of mice, chicken, pigs and primates with virus-like particles, naked RNA or layered DNA/RNA plasmids has provided protection against challenges with lethal doses of infectious agents and administered tumor cells. Both prophylactic and therapeutic efficacy has been achieved in cancer immunotherapy. Moreover, recombinant particles and replicon RNAs have been encapsulated by liposomes to improve delivery and targeting. Replicon RNA vectors have also been subjected to clinical trials. Overall, immunization with self-replicating RNA viruses provides high transient expression levels of antigens resulting in generation of neutralizing antibody responses and protection against lethal challenges under safe conditions.

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Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus

Cited by 33 publications

References 62 publications

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus

Replicon RNA Viral Vectors as Vaccines

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