MARINE SPONGE EXTRACT PEXTENOTOXIN-2 ABOLISHES CONSTITUTIVELY ACTIVATED NF-κB, LEADING TO SUPPRESSION OF NF-κB RELATED GENE PRODUCTS AND POTENTIATION OF APOPTOSIS  

Although pectenotoxin-2 (PTX-2) is known to modify the actin cytoskeleton, very little is known about its apoptosis mechanism. In this study, we investigated whether PTX-2 induces apoptotic effects through suppression of the NF-kappaB signaling pathway in several leukemia cell types. PTX-2 significantly induced growth inhibition and apoptosis in a dose-dependent manner. Treatment with PTX-2 also significantly increased caspase-3 activity and poly (ADP-ribose) polymerase (PARP) cleavage, however caspase-3 inhibitor z-DEVD-fmk significantly inhibited PTX-2-induced cell death. These data suggest that the activation of caspase-3 is associated with PTX-2-induced apoptosis. NF-kappaB has also been shown to inhibitapoptosis in response to chemotherapeutic agents. As examined by the DNA-binding of NF-kappaB activation, we found that PTX-2 suppressed constitutive NF-kappaB activation and determined by p65 and p50 nuclear translocation, and IkappaBalpha degradation through dephosphorylation of Akt. Attenuation of constitutive NF-kappaB activity by pretreatment with pyrrolidine dithiocarbamate (PDTC), an NF-kappaB nuclear translocation inhibitor, induced significantly apoptosis in the presence of PTX-2. In addition, treatment of PTX-2 down-regulated NF-kappaB-dependent geneexpression, Cox-2, IAP-1, IAP-2 and XIAP, at the transcriptional and translational level. Taken together, these results suggest that anti-cancer activities induced by PTX-2 may be mediated in part through suppression of constitutive NF-kappaB activity.