AZD8055 is a novel ATP-competitive inhibitor of mTOR kinase (both complexes mTORC1 and mTORC2) with an IC50 of 0.8 nM.Particularly,AZD8055 fully inhibited multisite eIF4E-binding protein1 phosphorylation,subsequently blocking protein translation, which was in contrast to the effects of rapamycin. In addition, the mTORC1-dependent PI3K/Akt feedback activation was fully abrogated in AZD8055-treated AML cells. Significantly, AZD8055 decreased AML blast cell proliferation and cell cycle progression, reduced the clonogenic growth of leukemic progenitors and induced caspase-dependent apoptosis in leukemic cells but not in normal immature CD34+ cells.
|Cell lines||H838 and A549 cells line|
|Preparation method||Growth inhibition and autophagy analysis. For growth inhibition and acridine staining, cells were exposed to increasing concentrations of AZD8055 for 72 to 96 h and stained for cell nuclei (0.03 mg/mL Hoechst 33342) and acidic vesicles (1 μg/mL acridine orange). Images were captured at 450 and 536 nm on an ArrayScan II (Cellomics) platform, and the percentage of acidic vesicles and the number of cells were quantified. For LC3 assessment, cells were exposed to e64d/pepstatin (10 μg/mL) for 30 to 90 min before incubation with AZD8055. Cells were lysed on ice and analyzed by immunoblotting.|
|Incubation time||72~96 h|
|Animal models||Mice bearing U87-MG xenografts or A549 xenografts|
|Formulation||dissolved in captisol (CyDex) and diluted to a final captisol concentration of 30% (w/v)|
|Dosages||0.1 mL/10 g of body weight once or twice daily|
|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.
|Source||Cell Death & Disease (2018). Figure 2. AZD8055 (Abmole Bioscience)|
|Method||colony formation assays|
|Cell Lines||MDA-MB-231, MDA-MB-157, and MDA-MB-468 cells|
|Incubation Time||24 h|
|Results||The results showed that AZD8055 or BEZ235 in combination with ABT263 strongly inhibited cell proliferation in different TNBC cell lines.|
|Source||Cell Death & Disease (2018). Figure 1. AZD8055 (Abmole Bioscience)|
|Cell Lines||TNBC cell lines|
|Incubation Time||24 h|
|Results||We found the mTOR inhibitors, especially the BEZ235 and AZD8055, could significantly inhibit the phosphorylation of AKT and 4EBP1 and efficiently led to decreasing MCL-1 expression.|
|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.|
Cell Death and Disease. 2018 Jan 26;9:137-52.
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1288-96.
Safety and tolerability of AZD8055 in Japanese patients with advanced solid tumors; a dose-finding phase I study.
Asahina et al. Invest New Drugs. 2012 Jul 28. PMID: 22843211.
Enhanced apoptosis and tumor growth suppression elicited by combination of MEK (selumetinib) and mTOR kinase inhibitors (AZD8055).
Holt et al. Cancer Res. 2012 Apr 1;72(7):1804-13. PMID: 22271687.
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