succinyl-alanylalanyl-prolyl-phenylalanine-chloromethylketone and Carcinoma

Protease inhibitors have been known to exhibit anticarcinogenic activity in a variety of model systems, although the biological target(s) and mechanism remain enigmatic. Human papillomavirus (HPV) is the primary etiological agent of cervical cancer. Here we show that a nuclear chymotrypsin-like protease activity (NCLPA), which appears to be involved in transformation in several different experimental models, is significantly elevated in keratinocytes infected with high-risk HPV. Further, we demonstrate a marked growth inhibition of organotypic raft cultures, which is specific for cells infected with high-risk HPV types, using a chloromethyl ketone inhibitor previously shown to be relatively selective for the NCLPA. Surprisingly, this HPV-dependent inhibitory effect is independent of any alterations in the NCLPA. This finding has clear implications for the development of novel therapeutics specifically targeted to cervical dysplasias with HPV-infected cells.

Topics: Amino Acid Chloromethyl Ketones; Carcinoma; Cell Culture Techniques; Cell Nucleus; Cell Proliferation; Cells, Cultured; Chymotrypsin; Dimethyl Sulfoxide; Dose-Response Relationship, Drug; Female; Genome, Viral; Humans; Keratinocytes; Male; Oligopeptides; Papillomaviridae; Papillomavirus Infections; Peptide Hydrolases; Protease Inhibitors; Uterine Cervical Neoplasms