Targeted Disruption of E6/p53 Binding Exerts Broad Activity and Synergism with Paclitaxel and Topotecan against HPV-Transformed Cancer Cells.

Abstract

Simple SummaryThe identification of new specific anti-human papillomavirus (HPV) drugs is highly needed, as HPV-induced cancers still represent a significant medical issue. The aim of this study was to analyze in more detail the therapeutic potential of a compound, Cpd12, that acts by blocking the binding between HPV E6 oncoprotein and cellular tumor suppressor p53. We demonstrated that by blocking such an interaction, driven by highly conserved residues among oncogenic HPVs, Cpd12 exhibits broad activity against cervical cancer cell lines infected by different HPV genotypes and HPV-positive head-and-neck cancer cells. Interestingly, Cpd12 also showed the ability to inhibit cancer cell migration and to increase the activity of chemotherapeutic drugs such as taxanes and topoisomerase inhibitors. These findings improve the knowledge about the in vitro efficacy of Cpd12, paving the way to preclinical studies to develop new therapeutic strategies against HPV-induced tumors.High-risk human papillomaviruses (HR-HPV) are the etiological agents of almost all cervical cancer cases and a high percentage of head-and-neck malignancies. Although HPV vaccination can reduce cancer incidence, its coverage significantly differs among countries, and, therefore, in the next decades HPV-related tumors will not likely be eradicated worldwide. Thus, the need of specific treatments persists, since no anti-HPV drug is yet available. We recently discovered a small molecule (Cpd12) able to inhibit the E6-mediated degradation of p53 through the disruption of E6/p53 binding in HPV16- and HPV18-positive cervical cancer cells. By employing several biochemical and cellular assays, here we show that Cpd12 is also active against cervical cancer cells transformed by other HR-HPV strains, such as HPV68 and HPV45, and against a HPV16-transformed head-and-neck cancer cell line, suggesting the possibility to employ Cpd12 as a targeted drug against a broad range of HPV-induced cancers. In these cancer cell lines, the antitumoral mechanism of action of Cpd12 involves p53-dependent cell cycle arrest, a senescent response, and inhibition of cancer cell migration. Finally, we show that Cpd12 can strongly synergize with taxanes and topoisomerase inhibitors, encouraging the evaluation of Cpd12 in preclinical studies for the targeted treatment of HPV-related carcinomas.