Identification of Anhydrodebromoaplysiatoxin as a Dichotomic Autophagy Inhibitor.

ABSTRACT

Dysfunctional autophagy is associated with various human diseases, e.g., cancer. The discovery of small molecules modulating autophagy with therapeutic potential could be significant. To this end, we screened the ability of a series of metabolites isolated from marine microorganisms to modulate autophagy. Anhydrodebromoaplysiatoxin (ADAT), a metabolite yielded by the marine red algae Gracilaria coronopifolia, inhibited autophagosome-lysosome fusion in mammalian cells, thereby inducing the accumulation of autophagosomes. Treatment of cells with ADAT alkalinized lysosomal pH. Interestingly, ADAT also activated the mTOR/p70S6K/FoxO3a signaling pathway, likely leading to the inhibition of autophagy induction. ADAT had little effect on apoptosis. Our results suggest that ADAT is a dichotomic autophagy inhibitor that inhibits both late-stage (autophagosome-lysosome fusion) and early-stage (autophagy induction) autophagy.