piperidines and Papillomavirus-Infections

New molecular therapeutic approaches have emerged in recent years for advanced gynaecological cancers, including targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi). These have demonstrated efficacy in high-grade serous ovarian cancers in patients carrying a mutation in the BRCA gene, which predisposes them to breast and ovarian cancers. Clinical and pre-clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway. These data raise the question of the potential efficacy of PARPi in advanced endometrial and cervical cancers where treatment options are currently limited. At present, there are few data available on the activity of PARPi in endometrial and cervical cancers, but some results seem promising. In this review, we present a synthesis of the available studies concerning PARPi in endometrial and cervical cancer.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cisplatin; Clinical Trials as Topic; DNA Damage; DNA Repair-Deficiency Disorders; Endometrial Neoplasms; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Papillomavirus Infections; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Uterine Cervical Neoplasms

Topics: Anal Canal; Animals; Anthracenes; Anus Neoplasms; Disease Models, Animal; Female; Male; Mice; Mice, Inbred NOD; Mice, SCID; Papillomaviridae; Papillomavirus Infections; Piperidines; Squamous Intraepithelial Lesions; Ultraviolet Rays

Topics: Anus Neoplasms; Colitis, Ulcerative; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Papillomaviridae; Papillomavirus Infections; Piperidines; Precancerous Conditions; Protein Kinase Inhibitors; Pyrimidines

Topics: Female; Humans; Middle Aged; Papillomavirus Infections; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Diseases, Viral

Human papillomavirus (HPV) infection is the major risk factor for anal dysplasia that may progress to squamous cell carcinoma of the anus. We have previously shown that systemic administration of a PI3K/mTOR inhibitor (BEZ235), an autophagic inducer, results in decreased squamous cell carcinoma of the anus in our HPV mouse model. In this study, we investigate the effect of the local, topical application of a BEZ235 on tumor-free survival, histopathology, PI3K/mTOR, and autophagy. The rationale for investigating a topical formulation is the localized nature of anal dysplasia/cancer and the goal for creating a clinically translatable formulation to decrease anal carcinogenesis. In this study, HPV transgenic mice were given no treatment, topical BEZ235, topical 7,12 dimethylbenz[a]anthracene (DMBA) (carcinogen), or both topical DMBA + BEZ235. Mice were assessed for tumor development and treatment-related toxicities. Tissue was evaluated for histology, PI3K/mTOR inhibition (pS6 and pAkt), and autophagy (LC3β and p62). DMBA-alone mice had an average of 16.9 weeks tumor-free survival, whereas mice receiving both DMBA+topical BEZ235 had 19.3 weeks (P < 0.000001). Histopathology revealed a significant decrease in dysplasia/carcinoma with the addition of topical BEZ235 to DMBA (P < 0.000001). Comparing DMBA versus DMBA + BEZ235, topical BEZ235 resulted in a significant decrease in both pS6 and pAkt (P < 0.001). Compared with no-treatment mice, both BEZ235-treated and DMBA + BEZ235-treated mice had significantly higher LC3β expression, signifying autophagic induction (P < 0.01), whereas DMBA-treated, BEZ235-treated, and DMBA+BEZ235-treated mice had a significantly lower p62 expression, signifying active autophagy (P < 0.0005). In conclusion, consistent with systemic delivery, topical application of BEZ235 shows decreased anal carcinogenesis through the activation of autophagy.

Topics: Administration, Topical; Animals; Anthracenes; Antineoplastic Agents; Anus Neoplasms; Apoptosis; Carcinogens; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Mice; Papillomaviridae; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Piperidines; Quinolines; TOR Serine-Threonine Kinases

Human papillomaviruses (HPV) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. In the present study several cervical carcinoma cell lines have been analyzed to investigate the expression of ET-1 and its receptors as well as their involvement in tumor growth. All HPV-positive cancer cells secreted ET-1 and expressed mRNA for ET-1 and its receptors, whereas a HPV-negative carcinoma cell line expressed only the ETBR mRNA and didn't secrete ET-1. Binding studies showed that HPV-associated cells expressed an increased number of functional ETAR. ET-1 stimulated a marked dose-dependent increase in [3H]-thymidine incorporation with respect to the normal cells whereas ET-3 and ETBR agonists had no effect. In HPV-positive cancer cells, a specific antagonist of ETAR inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumor cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR are increased and could be targeted for antitumor therapy.

Topics: Antineoplastic Agents; Binding, Competitive; Cell Division; Cell Line; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Oligopeptides; Papillomaviridae; Papillomavirus Infections; Peptides, Cyclic; Piperidines; Radioimmunoassay; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Tumor Cells, Cultured; Tumor Virus Infections; Uterine Cervical Neoplasms; Viper Venoms