ABT-737 is a potent and selective inhibitor of B-cell lymphoma-2 (BCL-2) family proteins. The ABT-737 single-agent LC90 values ranged from 100 nM for COG-LL-319 and RS4; 11 cells to low micromolar concentrations for the other five ALL cell lines. ABT-737 efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib. Moreover, we observed that the enhancement of ABT-737-mediated apoptosis by NCTD was associated with activation of mitochondrial apoptosis signaling pathway, which involved cytosolic release of cytochrome c, cleavage of caspase-9 and caspase-3. Finally, knockdown of Mcl-1 substantially potentiated ABT-737-mediated apoptotic cell death, confirming the potency of Mcl-1 repression by NCTD in enhancing ABT-737-induced apoptosis. These results therefore suggest that combination treatment with NCTD can overcome ABT-737 resistance and enhance ABT-737 therapeutic efficacy in treating human HCC.
|Cell lines||CLL cells and platelets|
|Preparation method||Apoptosis analysis Peripheral blood mononuclear cells were purified using Histopaque and cultured in RPMI 1640 medium supplemented with 10% fetal calf serum and 2 mmol/l L-glutamine at2*106 cells/ml. Cells were exposed to different concentrations of ABT-737, ABT-263, or ABT-199 for 4 h before analysis of apoptosis by externalisation of phosphatidylserine (PS) and binding of AnnexinV/fluorescein isothiocyanate (FITC). Platelets isolated from healthy volunteers were cultured in Hepes-buffered saline and exposed to different concentrations of ABT-737, ABT-263, or ABT-199 for 4 h before analysis of apoptosis in the CD41-positive population by externalisation of PS and binding of AnnexinV/FITC.|
|Incubation time||4 h|
|Animal models||C57BL/6 mice were injected (i.v.) with 3x106 T1 lymphoma cells|
|Formulation||formulated in 60% phosal 50PG (standardized phosphatidylcholine concentrate with at least 50% PC and propylene glycol|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥150 mg/mL|
Norcantharidin enhances ABT-737-induced apoptosis in hepatocellular carcinoma cells by transcriptional repression of Mcl-1.
Zhang et al. Cell Signal. 2012 Sep;24(9):1803-9. PMID: 22609455.
MEK inhibition enhances ABT-737-induced leukemia cell apoptosis via prevention of ERK-activated MCL-1 induction and modulation of MCL-1/BIM complex.
Konopleva et al. Leukemia. 2012 Apr;26(4):778-87. PMID: 22064351.
The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib.
Hikita et al. Hepatology. 2010 Oct;52(4):1310-21. PMID: 20799354.
|Related Bcl-2 Products|
BH3I-1 is a Bcl-XL-BH3 domain interaction inhibitor with Ki of 2.4 μM (by fluorescence polarization ).It is a selective inhibitor of Bcl-2 family proteins.
Obatoclax is an antagonist of Bcl-2 family members containing four Bcl-2 homology domains, including Bcl-2, Bcl-W, Bcl-XL, and Mcl-1 (KD = ~500 nM).
HA14-1 is a Bcl-2 inhibitor that is widely used for studies of apoptosis with IC50 of ~9 μM.
Sabutoclax(BI-97C1) is a pan-Bcl-2 inhibitor, including Bcl-xL, Bcl-2, Mcl-1 and Bfl-1 with IC50 of 0.31 μM, 0.32 μM, 0.20 μM and 0.62 μM, respectively.
BM-1074 is a potent and efficacious Bcl-2/Bcl-xL inhibitor with Ki of <1 nM, inactive to Mcl-1.
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