PAC-1

PAC-1 is a procaspase-3 activator that induces apoptosis in cancer cells with an EC₅₀ of 2.08 μM. IC50 & Target: EC50: 2.08 μM (procaspase-3)^[1] In Vitro: PAC-1 activates procaspase-3 with an EC₅₀ of 2.08 μM. PAC-1 exhibits an enhanced zinc chelating ability (EC₅₀= 7.08 μM). PAC-1 induces leukemia cell death with IC₅₀ of 4.03 μM, which is consistent with the values reported by other investigators. PAC-1 treatment also results in death of other malignant cells in a concentration-dependent manner with IC₅₀s ranging from 4.03 to 53.44μM. The overall mean IC₅₀ in the fifteen malignant cell lines is 0.88 mM for WF-210 and 19.40 μM for PAC-1. In contrast, the sensitivity of the normal human cells (PBL, L-02, HUVEC and MCF 10A) to WF-210 is 2.6-fold lower (mean IC₅₀=412.34 μM) than PAC-1 (mean IC₅₀=158.29 μM)^[1]. Procaspase-activating compound-1 (PAC-1) is the first direct caspase-activating compound discovered. PAC-1 treatment upregulates Ero1α in multiple cell lines, whereas silencing of Ero1α significantly inhibits calcium release from ER and cell death^[2]. In Vivo: To evaluate the in vivo effect of WF-210 on the growth of malignant tumors, we examined the ability of WF-210 to suppress tumor growth in mouse Hep3B and MDA-MB-435 xenograft models. These two cell lines express procaspase-3 at relatively high levels. Tumors induced by xenografts of the liver cancer cell Hep3B are allowed to develop and grow to a size of 100 mm³, after which WF-210 (2.5 mg/kg) or PAC-1 (5.0 mg/kg) is given daily for two weeks by intravenous (i.v.) administration. As shown in both PAC-1 and WF-210 significantly inhibits the growth of Hep3B tumor xenografts^[1].