Avarol

Avarol is a secondary metabolite from the marine sponge D. avara. It is a sequiterpenoid hydroquinone with potent cytotoxicity. Althoug resolving edoplasmic reticulum (ER) stress is essential for intracellular homeostasis, erratic or excessive ER stress can lead to apoptosis. Avarol selectively induces cell death in pancreatic ductual adenocarcinomas (PDAC), which are difficult to treat owing to the availability of few chemotherapeutic agents. The proposed MoA of avarol-induced apoptosis indicates upregulation of ER stress marker BiP and ER stress-dependent apoptosis inducer CHOP in PDAC cells but not in normal cells, suggesting that avarol selectively induces ER stress repsonses. It is shown, that avarol activates the PERK-elF2alpha pathway but did not affect the IRE1 and ATF6 pathways. Moreover, CHOP downregulation was significantly suppressed by avarol-induced apoptosis. Thus, the PERK-eIF2alpha-CHOP signaling pathway may be a novel molecular mechanism of avarol-induced apoptosis. The present data indicate that avarol has the potential as a chemotherapeutic agent for PDAC and induces apoptosis by activating the PERK-eIF2alpha pathway. Potential mode of action/Key words: Cytotoxic, Anticancer, Apoptosis inducer