Autophagy inhibitors deliver a knock-out blow

If you want to kill a tumor cell, prompting apoptosis is a good place to start. But don't stop there, say Degtyarev et al.: Wait a while, and then hit it again in the autophagosome.Figure 1 Numerous dense and enlarged autophagic vesicles (arrows) accumulate in tumor cells treated with chloroquine and Akt inhibitor.An inhibitor of apoptosis called Akt is overactive and contributes to uncontrolled growth in a wide variety of tumors. Akt inhibition is thus a leading anti-cancer strategy. But reducing Akt doesn't always increase apoptosis, suggesting there may be another side to its pro-survival activity. Recently, it was shown that Akt also suppresses autophagy, an alternative cell-death pathway. In the present study, the authors knocked down Akt in cancer cells and found that slowing of cell growth correlated with cell cycle delay and an increase in autophagy, supporting Akt's influence on this pathway. Nonetheless, as often observed in cancer treatment, many cells survived. “The cells seemed to hunker down,” says Kui Lin, who led the study—the increased autophagy appeared to allow the cells to cope with the metabolic stress induced by Akt suppression. Tricks that autophagy uses to slow down cell death include recycling of nutrients and scavenging of reactive oxygen species. The authors then asked whether inhibiting autophagy at the same time might deliver the knock-out blow. They found that inhibitors of the earliest stages of autophagosome formation had no effect, but the anti-malaria drug chloroquine, which inhibits the degradative function of autolysosomes, dramatically increased cell death. Affected cells accumulated grossly distorted autophagic vacuoles, lost their mitochondrial membrane potential almost completely, and suffered a large increase in reactive oxygen species within the cell, both a consequence of incomplete organelle destruction. The authors suggest that preventing digestion of autophagosome contents might help kill the cancer cells because the accumulating toxic debris could leak out. Whatever the reason, when tumors received this one-two punch of Akt suppression and chloroquine-induced autophagy disruption, tumor remission was substantially increased. Degtyarev, M., et al. 2008. J. Cell Biol. .10.1083/jcb.200801099 [PubMed] [Cross Ref]