As a consequence, E7 quickly leads to the stabilization of p53

and hence the need for E6:E6AP to neutralize p53 or lead to its ubiquitinylation and proteasome-mediated turnover. The selective mechanism of action of CDV as antiproliferative agent could be inferred by analysing the specific signatures identified in CDV-exposed PHKs that were not found in tumor cells, including cell cycle regulation and activation of DNA-double strand breaks (DSBs) repair mechanisms (i.e. ‘ATM Signalling’ and ‘Double-Strand Break Repair by Homologous Recombination’) (Fig. 12B). These findings suggest that CDV can generate double-strand DNA breaks that cannot be repaired Pexidartinib by tumor cells

but well by normal cells (De Schutter et al., 2013c). Furthermore, when we compared the efficiency of CDV incorporation into genomic DNA in the different cell types, higher amounts of CDV were incorporated in the genomic DNA of transformed epithelial cells compared to PHKs, despite the fact that the levels of intracellular CDV metabolites were not significantly different Selleck trans-isomer among the cell types investigated. Recently, these findings were confirmed by P. Hadaczek and co-workers who also found that CDV is incorporated into cellular DNA activating DNA damage response pathways due to increased DNA breaks that prompt elevated tumor cell apoptotic response in glioblastoma cells (Hadaczek et al., 2013). Besides differences in cell cycle regulation and DNA repair pathways, our gene expression profiling analysis also allowed the DOK2 identification of other pathways and functions that were induced or repressed following exposure to CDV differently in PHKs compared to HPV-positive and/or HPV-negative cells (De Schutter et al.,

2013c). For instance, Rho GTPase pathways and the acute phase response pathway were solely activated in immortalized cells while normal keratinocytes showed the activation of several metabolic pathways (Fig. 13). Therefore, besides induction of double-strand DNA breaks, CDV showed a differential effect on specific pathways in normal cells compared to transformed cells that may contribute to the activity and selectivity of the drug for tumor cells. Furthermore, in vitro acquisition of resistance to CDV in SiHa cells was found to implicate a variety of cellular functions and pathways linked to cell death, cell growth and differentiation, cellular movement, metabolism, tissue development as well as inflammatory response ( De Schutter et al., 2013b).