ENHANCED IN-VITRO CYTOTOXICITY AND CYTOSTASIS OF THE COMBINATION OF ONCONASE WITH A PROTEASOME INHIBITOR

In proliferating cells the turnover rare of proteins responsible for r egulation of the cell cycle progression, namely cyclins and inhibitors of the cyclin-dependent kinases (CDKs) and phosphatases, is rapid and their cellular level is modulated at the transcriptional. translation al and/or degradation (fia proteasome pathway) stages, inhibition of p roteasome function results in accumulation of rapidly turning over pro teins and, thus, causes all imbalance of the cell cycle regulatory com ponents, and loss of their regulatory function. Indeed, it has been sh own that proteasome inhibitors perturb the cell cycle progression. Onc onase. a novel RNase which has antitumor activity and is in clinical t rials, has; previously been shown to suppress protein synthesis. presu mably hv degradation of intracellular RNA, preferentially tRNA. By int erfering with regulation of expression of cyclins and/or CDK-inhibitor s, onconase also may induce the imbalance of these proteins and potent iate the effect of proteasome inhibitors. in the present study, we obs erved that the combinations of onconase with peptide-aldehyde inhibito rs of calpain and proteasome such as the N-acetyl-leucinyl-leucinyl-no rleucinal (LLnL) and the N-acetyl-leucinvl-valinyl phenylalaninal (LVP ), but not N-acetyl-leucinyl-leucinyl-methioninal (LLM, were synergist ic in suppressing cell proliferation and inducing apoptosis in three h uman tumor cell lines: A-549 lung adenocarcinoma. DU-145 prostatic car cinoma, and MDA-MB-231 breast carcinoma. The observed cytotoxicity may also be a result of prevention of the induction of the 'survival' gen es by the nuclear factor kappa B (NF kappa B) by onconase and proteaso me inhibitors. The data indicate that uch combinations should he furth er tested as potential anti cancer regimens.