Sudden Drug Resistance (SDR) In Cycloheximide-induced Apoptosis Of U937 Cells

Cycloheximide (CHX) is a typical protein synthesis inhibitor of eukaryotes. Since it can trigger apoptosis with the selection of cell types, and promote or inhibit apoptosis induced by various stimuli, CHX has been widely utilized in studies of the molecular mechanisms of apoptosis.In this study, we firstly described a novel form of chemoresistance, which we termed sudden drug resistance (SDR), in apoptosis of human leukeamic U937 cells. Then, our studies further suggested that SDR might be coupled to cell adhesion, especially to intercellular adhesion. Abrogating homotypic aggregation of U937 cells by various ways such as EDTA and anti-CD18 mAb preincubation would markedly increase CHX-induced U937 apoptosis and even result in the circumvention of SDR, whereas preincubation with plated ligands of ?2-integrins such as soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen would greatly prevent CHX-induced apoptosis and facilitate SDR. All these results indicate that ?2-integrin engagement is indeed a key mediator of SDR, but it may be non-exclusive, because plated ligands of other integrins such as fibronectin and RGDS tetrapeptide could accelerate SDR, too. Furthermore, the PI-3K inhibitor wortmannin sharply enhanced CHX-induced U937 apoptosis, further suggesting that PI-3K may participate in the downstream regulation of SDR.On the other hand, we also investigated the interrelationship between CHX and VP-16 on the induction of apoptosis. The results indicated that CHX could prevent VP-16-induced apoptosis by totally blocking de novo protein synthesis. Interestingly, VP-16 also strongly promoted CHX-induced U937 apoptosis and even circumvented SDR potentially through the activation of PKC?, but did not alter its selection of cell types. These findings may well explain why the inhibitory effects of CHX on apoptosis induced by the same stimuli are usually different according to the cell type used, and suggest that if CHX and other chemotherapeutic drugs are used in combination, a high percentage of quick and selective induction of apoptosis would be achieved to lower the side effects.