ABT-263, a novel, orally bioavailable, BH3 mimetic, binds with high affinity (Ki ≤ 1nM) and inhibits multiple antiapoptotic Bcl-2 family proteins. ABT-263 displays activity (EC50 ≤ 1µM) against human lymphoid and small cell lung cancer cell lines. Mechanism based preclinical toxicities include reductions in circulating lymphocytes, apoptosis of circulating platelets, and decreased spermatogenesis, mediated by inhibition of Bcl-2, Bcl-XL and Bcl-w with IC50 values of ≤ 1 nM, ≤0.5 nM and ≤ 1 nM, respectively.
|Cell lines||H1048 cells|
|Preparation method||Flourescence Activated Cell Sorting (FACS) for death assays and cell cycle analysis Cells were plated in triplicate in 6-well plates or 6-cm dishes to reach ~30-40% confluency the next day. On the next day, cells were treated with the indicated drugs or no drug control. Apoptosis and cell cycle experiments were performed essentially as previously described and analyzed on a BD LSR III (Becton Dickenson, Franklin Lanes, NJ). The cell cycle experiments were gated to include only viable cells in order for the cell cycle distribution to be determined from this population. For apoptosis assays, the number of cells in quadrants II and IV (Annexin positive) were counted as apoptotic, where cells with subG0/G1 DNA3 were quantified and counted as apoptotic following staining with PI. The Annexin stain was conjugated to FITC and the analysis was done on a Guava easyCyte flow cytometer (EMD Millipore (Temecula, CA)). In the engineered H1048 cells, apoptosis determined by ABT-263 treatment and combination ABT-263/AZD8055 treatment were performed within the same experiment.|
|Concentrations||500 nM AZD8055, 1 μM ABT-2631|
|Animal models||Traditional human cell-line xenograft(6-10 week-old mice with a Nu/Nu background with exponentially growing NCI-H1048 or NCI-H82 cells into the right rear flanks)|
|Formulation||AZD8055 was dissolved in Captisol ®. ABT-263 was dissolved in a mixture of 60% Phosal 50 PG, 30% PEG 400 and 10% EtOH.|
|Dosages||16 mg/kg/qd AZD8055, 80 mg/kg/qd ABT-263|
|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 ≥180 mg/mL|
|Source||Clin Cancer Res (2017). Figure 4. ABT-263 (Abmole Bioscience)|
|Cell Lines||Mice harboring H1975 ER-TWIST+4-OHT tumors|
|Incubation Time||5 d|
|Results||The pharmaceutical approach of combining ABT-263 and an EGFRi could be successful in both EGFR mutant lung cancers with EMT-mediated acquired resistance, as well as mesenchymal cancers in the upfront setting.|
|Source||Proc Natl Acad Sci U S A. (2015). Figure 3. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Method||FACS analysis(Apoptosis), Western blotting, Immunoprecipitation (IP),Traditional human cell-line xenograft experiments|
|Cell Lines||SCLC H82 and H1048 cells|
|Concentrations||500 nM AZD8055, 1 μM ABT-263|
|Incubation Time||2,16, 72h|
|Results||Combination treatment with ABT-263 and the TORC1/2 inhibitor AZD8055 leads to robust apoptosis and antitumor activity in vivo.|
|Source||Proc Natl Acad Sci U S A. (2015). Figure 2. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Method||FACS analysis(Apoptosis),quantitative (q)RT-PCR, Western blotting, Immunoprecipitation (IP)|
|Cell Lines||SCLC SW1271 and H1048 cells|
|Results||BIM and MCL-1 mediate ABT-263–induced apoptosis in SCLC, and the ratio of BIM to MCL-1 expression predicts the magnitude of apoptosis in SCLC cell lines.|
|Source||Proc Natl Acad Sci U S A. (2015). Figure 1. ABT-263 and AZD8055 were purchased from Active Biochemicals (Hong Kong, China) and Abmole Bioscience (Houston, TX)|
|Cell Lines||SCLC cell lines|
|Results||we found a modest, but significant, correlation between BIM expression and sensitivity to ABT-263.ABT-263 across both data sets (SI Appendix, Fig. S1 B and C). However, the ratio of BIM to MCL-1 predicted sensitivity to ABT-263 more effectively than the expression of either biomarker alone. SCLC lines have increased BIM expression compared with other solid tumor types along with enhanced sensitivity to ABT-263 compared with other solid tumor types across a large panel of cancer cell lines.|
Clin Cancer Res. 2017 Oct 19;pii: clincanres.1577.2017.
Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM
ABT-263 purchased from AbMole
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1288-96.
Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.
Faber AC,et.al. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11). PMID: 25737542.
Efficient elimination of cancer cells by deoxyglucose-ABT-263/737 combination therapy.
Yamaguchi et al. PLoS One. 2011;6(9):e24102. PMID: 21949692.
Navitoclax (ABT-263) accelerates apoptosis during drug-induced mitotic arrest by antagonizing Bcl-xL.
Shi et al. Cancer Res. 2011 Jul 1;71(13):4518-26. PMID: 21546570.
Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors.
Gandhi et al. J Clin Oncol. 2011 Mar 1;29(7):909-16. PMID: 21282543.
Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines.
Tahir et al. Mol Cancer Ther. 2010 Mar;9(3):545-57. PMID: 20179162.
|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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