Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity.

[1]  C. Kevil,et al.  Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway. , 2010, Cardiovascular research.

[2]  R. Martuza,et al.  Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures , 2009, Gene Therapy.

[3]  R. Martuza,et al.  Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells , 2009, Cancer Gene Therapy.

[4]  Khalid Shah,et al.  Human glioblastoma-derived cancer stem cells: establishment of invasive glioma models and treatment with oncolytic herpes simplex virus vectors. , 2009, Cancer research.

[5]  D. Kirn,et al.  Development of targeted oncolytic virotherapeutics through translational research , 2008 .

[6]  T. Chou,et al.  Synergy of a Herpes Oncolytic Virus and Paclitaxel for Anaplastic Thyroid Cancer , 2008, Clinical Cancer Research.

[7]  Hyung-Hwan Kim,et al.  Translational therapeutics of dipyridamole. , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[8]  J. Buolamwini,et al.  Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibitors. , 2007, Journal of medicinal chemistry.

[9]  P. Philip,et al.  Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Stephen A Baldwin,et al.  Nucleoside transporters: from scavengers to novel therapeutic targets. , 2006, Trends in pharmacological sciences.

[11]  H. Fukuhara,et al.  Triple gene-deleted oncolytic herpes simplex virus vector double-armed with interleukin 18 and soluble B7-1 constructed by bacterial artificial chromosome-mediated system. , 2005, Cancer research.

[12]  Prasad Adusumilli,et al.  Up‐regulation of GADD34 mediates the synergistic anticancer activity of mitomycin C and a γ134.5 deleted oncolytic herpes virus (G207) , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  Lijun Xue,et al.  The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53. , 2003, Cancer research.

[14]  K. Delman,et al.  Functional Interaction between Fluorodeoxyuridine-Induced Cellular Alterations and Replication of a Ribonucleotide Reductase-Negative Herpes Simplex Virus , 2001, Journal of Virology.

[15]  R. Martuza,et al.  Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Thomas D. Y. Chung,et al.  A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays , 1999, Journal of biomolecular screening.

[17]  S. Yao,et al.  Cloning of a human nucleoside transporter implicated in the Cellular uptake of adenosine and chemotherapeutic drugs , 1997, Nature Medicine.

[18]  S. Elledge,et al.  Ribonucleotide reductase: regulation, regulation, regulation. , 1992, Trends in biochemical sciences.

[19]  D M Coen,et al.  Experimental therapy of human glioma by means of a genetically engineered virus mutant , 1991, Science.

[20]  B. Roizman,et al.  Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. , 1990, Science.