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

Brent J. Passer, Tooba Cheema, Bingsen Zhou, Hiroaki Wakimoto, Cecile Zaupa, Mani Razmjoo, Jason Sarte, Shulin Wu, Chin Lee Wu, James W. Noah, Qianjun Li, John K. Buolamwini, Yun Yen, Samuel D. Rabkin, Robert L. Martuza

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21 Citations (Scopus)

Abstract

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 G47Δ. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Δ 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.

Original languageEnglish
Pages (from-to)3890-3895
Number of pages6
JournalCancer Research
Volume70
Issue number10
DOIs
Publication statusPublished - May 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Passer, B. J., Cheema, T., Zhou, B., Wakimoto, H., Zaupa, C., Razmjoo, M., Sarte, J., Wu, S., Wu, C. L., Noah, J. W., Li, Q., Buolamwini, J. K., Yen, Y., Rabkin, S. D., & Martuza, R. L. (2010). Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Research, 70(10), 3890-3895. https://doi.org/10.1158/0008-5472.CAN-10-0155