Evaluation of apoptosis of a new histone de Acetylase inhibitor (HDACi 1-2), in comparation with the commercial Vorinostat, in Cervical Cancer cells associated with Human PapillomaVirus (HPV)

Abstract

The role epigenetic modifications on carcinogenesis process have received a lot of attention in the last years. Among those , the histones acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation and cell death, and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, nonenveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPVs types, mainly HPV16 and HPV18, is one of the major risk factor responsible to promote cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. The present study aims to verify the activity of a newly synthesized molecule of histone deacetylase HDACi 1/2 compares the commercial drug Vorinostat that also inhibits this same class of HDAC, comparatively evaluating its effect or synergism in cervical cancer cells associated with HPV 16 (SiHa and Caski) and respective cell controls - HPV negative cervical cancer cell line (C33-A) and spontaneously immortalized normal skin keratinocyte (HaCaT). The experiments will be carried out by cytotoxicity tests to MTT, determining the dose-response concentration and time-response of both compounds (new molecule and commercial compound), as well as to determine the IC50 to later evaluate the potential synergistic effect of both. Then, apoptosis and cell proliferation tests will be performed, checking the in vitro antitumor capacity of these compounds for cervical cancer associated with HPV. (AU)