The B-cell lymphoma 2 (Bcl-2) family of proteins is composed of both antiapoptotic members, such as Bcl-2, Bcl-xL as well as Bcl-w, and proapoptotic members. Up-regulation of the pro-survival Bcl-2 family proteins is one of the primary means for cancer cells to evade apoptosis. ABT-737 is a selective inhibitor of Bcl-2 family with EC50 values of 78.7nM, 30.3nM and 198.8nM for BCL-XL, BCL-2 and BCL-W (measured by FP assay), respectively, with almost no inhibition on BCL-B, BFL-1 and MCL-1. ABT-737 can inhibit cell growth with IC50 values of 50nM, 80nM, 80nM, 2μM and 5μM for leukemic cells HL60, KG1, NB4, U937 and OCI-AML3 cells, as well as and induce apoptosis at dose of 100nM for 12 or 24h in HL60. As a BH3 mimetic small-molecule, the in vitro studies showed that ABT-737 disrupted BCL-2/BAX heterodimerization and improved the apoptosis throuth inducing BAX change to a “prodeath’’ conformation in AML cells. Both inhibition of BCL-2 phosphorylation and suppression of MCL-1 expression could enhance ABT-737-mediated apoptosis. Intraperitoneal administration of ABT-737 at dose of 20 and 30mg/kg suppressed the leukemia burden by 48% and 53%, respectively, as well as significantly extended survival of leukemia model. A similar inhibition of leukemia burden was also observed in a human xenograft leukemia model with KG-1 cells[1].
作用机制
ABT-737 is a BH3 mimetic small-molecule that can occupies the BH3 binding groove of BCL-2.[1]
ABT-737 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human CD34+ cells
5 µM
24 hours
Assess sensitivity to different cytotoxic drugs with BCL-XL inhibition, showing increased sensitivity to ER stress and pan-kinase inhibition.
Cell Death Dis. 2020 Jan 6;11(1):8.
Meg-01 cells
20 μM
ABT-737 significantly sensitized Meg-01 cells to IR-induced apoptosis
Mil Med Res. 2023 Dec 19;10(1):66.
HUVEC cells
500 nM
2 h
ABT-737 significantly reduced tubule formation in HUVEC cells
Clin Cancer Res. 2009 Oct 1;15(19):6096-105.
MCF10A cells
100 nM
24 h
To test the apoptotic effect of ABT-737 in combination with AMPK activator A-769662, results showed that ABT-737 combined with A-769662 significantly enhanced apoptosis when MYC was activated.
Nat Commun. 2019 Feb 6;10(1):620.
T-ALL cell lines
0.8 µM
48 h
To detect ABT-737-induced apoptosis, results showed that Fbw7-deficient T-ALL cells were resistant to ABT-737
Nature. 2011 Mar 3;471(7336):104-9.
HLE cells
5 µM
8 h
ABT-737 in combination with sorafenib did not significantly increase cell death in HLE cells.
Cell Death Dis. 2021 Jul 26;12(8):736.
Huh7 cells
5 µM
8 h
ABT-737 in combination with sorafenib significantly reduced cell viability and increased caspase activation in Huh7 cells.
Cell Death Dis. 2021 Jul 26;12(8):736.
Hep3B cells
5 µM
8 h
ABT-737 in combination with sorafenib significantly increased cell death and caspase activation in Hep3B cells.
Cell Death Dis. 2021 Jul 26;12(8):736.
H460 cells
500 nM
2 h
ABT-737 induced caspase-3 cleavage, promoting apoptosis in H460 cells and significantly enhancing their sensitivity to radiation
Clin Cancer Res. 2009 Oct 1;15(19):6096-105.
ABT-737 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NPG mice
T-ALL mouse model
Intravenous injection
40 mg/kg
Twice a week for 4 weeks
To evaluate the efficacy of IRAK/ABT-NP in T-ALL mouse model, results showed that IRAK/ABT-NP significantly restored white blood cell count in peripheral blood and improved the survival time of mice
Int J Nanomedicine. 2017 Oct 31;12:8025-8034
Mice
Radiation injury-induced thrombocytopenia model
Intraperitoneal injection
30 mg/kg
Immediately administered, duration not specified
ABT-737 significantly sensitized mice to IR-induced apoptosis, leading to a significant decline in platelet counts and size
Mil Med Res. 2023 Dec 19;10(1):66.
Mice
WapMyc breast cancer model
Intraperitoneal injection
100 mg/kg
Once daily for 21 days
To evaluate the antitumor effect of ABT-737 in the WapMyc breast cancer model, results showed that ABT-737 inhibited tumor growth in the early stages of treatment but did not significantly improve survival.
The combination of ABT-737 and rapamycin significantly extended tumor growth delay, increased caspase-3 activity, and reduced p62 protein levels, indicating enhanced apoptosis and autophagy
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