Cephalostatin 1-induced apoptosis in tumor cells by selective induction of Smac/DIABLO release

Cephalostatin 1 is a marine bis-steroidal compound with strong (mean panel GI50: 2.2 (± 1.21) x 10-9 M) and particular cytotoxic activity as shown in the in vitro 60-cell line screen by the National cancer Institute (USA). Cephalostatin 1 was shown to trigger cell death in human Jurkat T cells with classical morphological (cell shrinkage, membrane blebbing, DNA fragmentation) and biochemical (phosphatidylserine translocation, activation of caspases) signs of apoptosis. Cephalostatin 1-induced apoptosis, however, differs significantly from apoptosis induced by classical chemotherapeutic drugs in that it selectively leads to Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point) release from mitochondria. Cytochrome c and apoptosis inducing factor (AIF) is retained in the mitochondrial intermembrane space. Selectively released Smac/DIABLO translocates into the cytosol where it binds to XIAP displacing previously bound caspase-9. Caspase-9 does not associate with Apaf-1 and thus appears to be processed without requirement for apoptosome formation. This unique mitochondrial signaling by cephalostatin 1 is accompanied by mitochondrial matrix condensation instead of mitochondrial swelling. Swelling is assumed to precede outer mitochondrial membrane permeabilization in response to induction of the mitochondrial (intrinsic) apoptosis pathway. These results characterize cephalostatin 1 as a remarkable experimental chemotherapeutic agent with a unique mechanism of action. Further studies will show whether cephalostatin 1 will be a good candidate to be developed against chemoresistant types of cancer.