An atypical necrotic signal induced by immunosuppressive and anti-viral agents

We recently demonstrated that the anti-viral agent ribavirin and the immunosuppressor mycophenolic acid (MPA) are both potent inducers of a necrotic signal. These two chemicals deplete the intracellular pool of guanosine triphosphate through the inhibition of inosine monophosphate dehydrogenase (IMPDH) activity. The cellular stress resulting from the GTP/GDP depletion leads to the activation of the small GTPase Cdc42 and the remodeling of actin, which are crucial events in the transmission of the MPA-mediated necrotic signal. Nevertheless, we observe for each tested cell (leukemic T and B-cell lines, activated PBLs) that a minor part of the cell population is killed through a caspase-dependent apoptotic signal. Blockade of the caspase activity eliminates the apoptotic cells, which are replaced by cells exhibiting autophagic features. In light of our findings, we assume that the newly characterized atypical cell death induced by MPA may account for the decreased risk of cancer occurrence observed in transplant recipients treated with mycophenolate mofetil (MMF) versus a non-MMF regimen.