HIV protease inhibitors block oral epithelial cell DNA synthesis

Robert J. Danaher, Chunmei Wang, Andrew T. Roland, Charlotte S. Kaetzel, Richard N. Greenberg, Craig S. Miller

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Objectives: Anti-retroviral therapy regimens that include HIV protease inhibitors (PIs) are associated with diverse adverse effects including increased prevalence of oral warts, oral sensorial deficits and gastrointestinal toxicities suggesting that PIs may perturb epithelial cell biology. To test the hypothesis that PIs could affect specific biological processes of oral epithelium, the effects of these agents were evaluated in several oral epithelial cell-lines. Design: Primary and immortalized oral keratinocytes and squamous carcinoma cells of oropharyngeal origin were cultured in the presence of pharmacologically relevant concentrations of PIs. Their affects on cell viability, cytotoxicity and DNA synthesis were assessed by enzymatic assays and incorporation of 5-bromo-2′-deoxyuridine (BrdU) into DNA. Results: Viability of primary and immortalized oral keratinocytes as well as squamous carcinoma cells of oropharyngeal origin was significantly reduced by select PIs at concentrations found in plasma. Of the seven PIs evaluated, nelfinavir was the most potent with a mean 50% inhibitory concentration [IC50] of 4.1 μM. Lopinavir and saquinavir also reduced epithelial cell viability (IC50 of 10-20 μM). Atazanavir and ritonovir caused minor reductions in viability, while amprenavir and indinavir were not significant inhibitors. The reduced cell viability, as shown by BrdU incorporation assays, was due to inhibition of DNA synthesis rather than cell death due to cytotoxicity. Conclusion: Select PIs retard oral epithelial cell proliferation in a drug and dose-dependent manner by blocking DNA synthesis. This could account for some of their adverse effects on oral health.

Original languageEnglish
Pages (from-to)95-100
Number of pages6
JournalArchives of Oral Biology
Volume55
Issue number2
DOIs
StatePublished - Feb 2010

Bibliographical note

Funding Information:
Funding: This investigation was supported by Research Grant R21 DE018332 to CSM from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.

Keywords

  • Epithelial cells
  • HAART
  • Protease inhibitors
  • Viability

ASJC Scopus subject areas

  • Otorhinolaryngology
  • Dentistry (all)
  • Cell Biology

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