Upregulation of mcl 1 could be involved in nelfinavir mediated cytoprotection of sev eral untransformed cell types, although we did not observe significant endogenous mcl 1 e pression or even Inhibitors,Modulators,Libraries nelfinavir induced mcl 1 upregulation in bone marrow fibroblasts or leukocytes. In some previous studies, the mitochondria protective effect of nelfinavir was found to be indepen dent of protein synthesis and to be mediated by direct binding of nelfinavir to the adenine nucleotide translocase, a subunit of the mitochon drial permeability transition pore comple . Thus, nelfinavir mediated mitochondria protection and cell death can be modulated by various mechanisms that might vary among cell types and species.

Interest ingly, a similar parado ical effect has been observed for glucocorticoids, which induce apoptosis in leukemia cells but protect normal and cancerous epithelial cells by upregulating anti apopto tic proteins. However, the prospect of nelfinavir as a multipotent cytoprotective agent with selective anti cancer activity should Inhibitors,Modulators,Libraries be considered with caution and may be an unachievable benchmark for this drug. We have observed that higher doses of nelfinavir can indeed induce cell damage in human bone marrow cells and, thus, nelfinavir should not be AV-951 regarded as a bone marrow protective drug. Still, the nelfinavir concentration Inhibitors,Modulators,Libraries necessary to induce high levels of apoptosis in leukemia cells showed only a limited effect on bone marrow cells, thus providing a potential therapeutic concentration for efficient leukemia treat ment with reduced adverse effects on the bone mar row.

This is especially important given that the bone marrow is already damaged in leukemia patients Inhibitors,Modulators,Libraries after standard first and second line high dose chemothera pies with myelosuppressive drugs. These data, as well other reports, indicate that the concentration of nelfinavir appears to be of crucial importance for its effect as either a cytoprotective drug or a cell death inducing agent. In HIV infected persons treated with nelfinavir, individual nelfinavir plasma concentrations were found to be highly variable, with a mean average drug plasma concentration of 2. 22 1. 25 ug m. This level is below the concentration that induces death of leukemia cells or other cancer cells. In fact, a recent study on the occurrence of can cer in nelfinavir treated HIV patients revealed no reduced cancer risk, confirming that these con centrations are sub optimal for cancer treatment. However, the plasma concentrations occurring in HIV patients have been specifically adapted for efficient and long term HIV protease inhibition. Administering higher oral doses of nelfinavir or applying nelfinavir via an intravenous route can significantly enhance plasma nelfinavir concentrations.