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Enhancement of oncolytic virotherapy by vanadium(V) dipicolinates

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Abstract

Oncolytic viruses rewire the immune system and can lead to long-lasting antitumor defenses against primary and metastatic tumors. However, results from clinical studies have shown heterogeneity in responses suggesting that multiplexed approaches may be necessary to consistently generate positive outcomes in patients. To this end, we explored the combination of oncolytic rhabdovirus VSV∆51 with vanadium(V) dipicolinate derivatives, which have already been explored for their antidiabetic properties in animal models. The combination of vanadium-based dipicolinate compounds with VSV∆51 significantly increased viral replication and cytotoxicity in the human renal cell carcinoma cell line 786-0. The effects of three vanadium(V)-dipicolinate coordination complexes ([VO2dipic]−, [VO2dipic-OH]− and [VO2dipic-Cl]− with –OH or –Cl in the para position) were compared to that of the simple salts using spectroscopy and speciation profiles. Like the vanadate salts and the vanadyl cation, all dioxovanadium(V) dipicolinate complexes tested were found to increase viral infection and cytotoxicity when used in combination with VSV∆51. Viral sensitization is dependent on the vanadium since free dipicolinate ligands exerted no effect on viral infection and viability. The ability of these complexes to interact with interfaces and the stability of the complexes were evaluated under physiological conditions. Results indicate that these complexes undergo hydrolysis in cell culture media thereby generating vanadate. The vanadium dipicolinate derivatives in the context of immunovirotherapy shares similarities with previous studies exploring the antidiabetic properties of the compounds. The synergy between vanadium compounds and the oncolytic virus suggests that these compounds may be valuable in the development of novel and effective pharmaco-viral therapies.

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Abbreviations

AOT:

Sodium aerosol-OT (sodium salt of bis(2-ethylhexyl)sulfosuccinate)

BEOV:

Bis(ethylmaltolato)oxovanadium(IV)

BMOV:

Bis(maltolato)oxovanadium(IV)

DSS:

3-Trimethylsilyl-1-propanesulfonic acid sodium salt

H2dipic:

Dipicolinic acid, 2,6-pyridinedicarboxylic acid

H2dipic-OH:

4-Hydroxydipicolinic acid

H2dipic-Cl:

4-Chlorodipicolinic acid

HPI:

Hours post infection

GFP:

Green fluorescent protein

MOI:

Multiplicity of infection

OV:

Oncolytic virus

T-VEC:

Talimogene laherparepvec

[VO2dipic]− :

Dioxovanadium(V) dipicolinate

[VO2dipic-OH]− :

Dioxovanadium(V) 4-hydroxydipicolinate

[VO2dipic-Cl]− :

Dioxovanadium(V) 4-chlorodipicolinate

VSV:

Vesicular stomatitis virus

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Acknowledgements

AB holds a QEII Ontario Graduate Scholarship and a Hans K. Uhtoff scholarship. MS was awarded a Canadian Institutes of Health Research (CIHR) doctoral scholarship. JSD thanks Terry Fox Research Institute Program Project grant for funding. JSD also holds a New Investigator award from CIHR in Infection and Immunity. DCC received funding from the Arthur Cope foundation administered by the American Chemical Society. The authors thank all funding agencies for their generous support of scholarships and grants.

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Authors and Affiliations

  1. Center for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Anabel Bergeron, Mohammed Selman, Naveen Haribabu, Rozanne Arulanandam & Jean-Simon Diallo

  2. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada

    Anabel Bergeron, Mohammed Selman & Jean-Simon Diallo

  3. Department of Chemistry, Colorado State University, Fort Collins, CO, USA

    Kateryna Kostenkova, Heide A. Murakami, Elizabeth Owens & Debbie C. Crans

  4. Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA

    Debbie C. Crans

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  1. Anabel Bergeron
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  2. Kateryna Kostenkova
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  3. Mohammed Selman
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Bergeron, A., Kostenkova, K., Selman, M. et al. Enhancement of oncolytic virotherapy by vanadium(V) dipicolinates. Biometals 32, 545–561 (2019). https://doi.org/10.1007/s10534-019-00200-9

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