Bcl-2 (B-cell lymphoma 2) is an integral outer mitochondrial membrane protein that regulates cell death by inhibiting Bax, thus controlling the mitochondrial membrane permeability. Bcl-2 could engage a group of proapoptotic Bcl-2 family members, the BH3-only proteins like Bid and Bim, by physically sequestering them from directly activating Bax. Bcl-2 could also interact with Bax directly[3].
HA14-1 is an inhibitor of Bcl-2. In a binding assay, HA14-1 was found to bind the designated pocket on Bcl-2 with the IC50 of ≈ 9 μM in competing with the bcl-2 binding of Flu-BakBH3[4]. In a MTT assay, the lethal concentration 50% (LC50) values of HA14-1 to HF1A3, HF4.9 and HF28RA cells when incubated for 20h were 4.5 μM, 12.6 μM and 8.1 μM, respectively[5]. Treatment with 50 μM HA14-1 by 3h induced apoptosis in HL-60 cells as evidenced by DNA ladders[4].
In a BeGBM xenograft model established in nude mice, HA14-1 was injected once weekly for 4 weeks at the concentration of 400 nM in 100 μl volume at the site of cell injection. This dose of HA14-1 increased the effect of etoposide on tumor growth[3].
作用机制
HA14-1 is an inhibitor of Bcl-2. In a binding assay, HA14-1 was found to bind the designated pocket on Bcl-2 with the IC50 of ≈ 9 μM in competing with the bcl-2 binding of Flu-BakBH3[4].
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