Cidofovir is active against human papillomavirus positive and negative head and neck and cervical tumor cells by causing DNA damage as one of its working mechanisms

Abstract

// Barbara Mertens 1 , Tatiane Nogueira 1 , Ruzena Stranska 1 , Lieve Naesens 1 , Graciela Andrei 1 , Robert Snoeck 1 1 Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium Correspondence to: Barbara Mertens, email: barbara.mertens@kuleuven.be Keywords: human papillomavirus, cidofovir, DNA damage, incorporation, antiproliferative effects Received: January 28, 2016      Accepted: June 04, 2016      Published: June 16, 2016 ABSTRACT Human papillomavirus (HPV) causes cervical cancer and a large fraction of head and neck squamous cell carcinomas (HNSCC). Cidofovir (CDV) proved efficacious in the treatment of several HPV-induced benign and malignant hyper proliferations. To provide a better insight into how CDV selectively eradicates transformed cells, HPV + and HPV − cervical carcinoma and HNSCC cell lines were compared to normal cells for antiproliferative effects, CDV metabolism, drug incorporation into cellular DNA, and DNA damage. Incorporation of CDV into cellular DNA was higher in tumor cells than in normal cells and correlated with CDV antiproliferative effects, which were independent of HPV status. Increase in phospho-ATM levels was detected following CDV exposure and higher levels of γ-H2AX (a quantitative marker of double-strand breaks) were measured in tumor cells compared to normal cells. A correlation between DNA damage and CDV incorporation into DNA was found but not between DNA damage and CDV antiproliferative effects. These data indicate that CDV antiproliferative effects result from incorporation of the drug into DNA causing DNA damage. However, the anti-tumor effects of CDV cannot be exclusively ascribed to DNA damage. Furthermore, CDV can be considered a promising broad spectrum anti-cancer agent, not restricted to HPV + lesions.