Caspases are a family of cysteinyl aspartate-specific proteases that are highly conserved in multicellular organisms and function as central regulators of apoptosis. A member of this family, caspase-3, has been identified as a key mediator of apoptosis in neuronal cells[1]. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death[2]. Caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU.[3]. CASP3 Activator 1541 is an activator of the proenzyme forms of caspase-3, which can induce cell death. Compound 1541 self-assembles into nanofibrils, and localization of procaspase-3 to the fibrils promotes activation. Experiment showed that fibril-induced colocalization of trace amounts of caspase-3 or other initiator proteases with procaspase-3 dramatically stimulates maturation of the proenzyme in vitro[4].
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