title: Cidofovir selectivity is based on the different response of normal and cancer cells to DNA damage.
abstract: BACKGROUND
  Cidofovir (CDV) proved efficacious in treatment of human papillomaviruses (HPVs) hyperplasias. Antiproliferative effects of CDV have been associated with apoptosis induction, S-phase accumulation, and increased levels of tumor suppressor proteins. However, the molecular mechanisms for the selectivity and antitumor activity of CDV against HPV-transformed cells remain unexplained.
  
  
  METHODS
  We evaluated CDV drug metabolism and incorporation into cellular DNA, in addition to whole genome gene expression profiling by means of microarrays in two HPV(+) cervical carcinoma cells, HPV- immortalized keratinocytes, and normal keratinocytes.
  
  
  RESULTS
  Determination of the metabolism and drug incorporation of CDV into genomic DNA demonstrated a higher rate of drug incorporation in HPV(+) tumor cells and immortalized keratinocytes compared to normal keratinocytes. Gene expression profiling clearly showed distinct and specific drug effects in the cell types investigated. Although an effect on inflammatory response was seen in all cell types, different pathways were identified in normal keratinocytes compared to immortalized keratinocytes and HPV(+) tumor cells. Notably, Rho GTPase pathways, LXR/RXR pathways, and acute phase response signaling were exclusively activated in immortalized cells. CDV exposed normal keratinocytes displayed activated cell cycle regulation upon DNA damage signaling to allow DNA repair via homologous recombination, resulting in genomic stability and survival. Although CDV induced cell cycle arrest in HPV- immortalized cells, DNA repair was not activated in these cells. In contrast, HPV(+) cells lacked cell cycle regulation, leading to genomic instability and eventually apoptosis.
  
  
  CONCLUSIONS
  Taken together, our data provide novel insights into the mechanism of action of CDV and its selectivity for HPV-transformed cells. The proposed mechanism suggests that this selectivity is based on the inability of HPV(+) cells to respond to DNA damage, rather than on a direct anti-HPV effect. Since cell cycle control is deregulated by the viral oncoproteins E6 and E7 in HPV(+) cells, these cells are more susceptible to DNA damage than normal keratinocytes. Our findings underline the therapeutic potential of CDV for HPV-associated malignancies as well as other neoplasias.
authors.affiliation: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: De Schutter
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Dimitri
authors.initials: D
authors.lastname: Topalis
authors.forename: Lieve
authors.initials: L
authors.lastname: Naesens
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000998:Antiviral Agents / Q000633:toxicity*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D000077404:Cidofovir; D019295:Computational Biology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000633:toxicity; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000633:toxicity*; D027383:Papillomaviridae / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D047488:Retinoid X Receptors; D003596:Cytosine; D020741:rho GTP-Binding Proteins; D000077404:Cidofovir