BEZ235 (NVP-BEZ235) is a potent dual inhibitor of PI3K and mTOR. BEZ235 (NVP-BEZ235) is able to effectively and specifically block the dysfunctional activation of the PI3K pathway and induce G (1) arrest. It also inhibits the growth of human cancer in animal models. For Class I PI3K family, NVP-BEZ235 biochemical IC50 are 4nM against p110α, 75nM against p110β, 7nM against p110σ, 5nM against p110γ.
|Cell lines||MKN45, BT474, SNU216 and NCI-N87 cell lines|
|Preparation method||Cell viability assay Cells were seeded at a density of 2000 cells per well in a 96-well plate and incubated overnight in complete medium. Cells were treated with either trastuzumab, BEZ235, Everolimus, AZD6244 alone, or trastuzumab combined with BEZ235 or Everolimus or AZD6244. After 72 h of incubation, cell viability was determined using the MTS tetrazolium substrate (CellTiter 96 Aqueous One Solution Cell Proliferation Assay, Promega, Madison, WI, USA) following the manufacturer’s instructions. The absorbance was measured at 490 nm using a spectrophotometer. All experiments were repeated three times with at least triplicate readings for each concentration.|
|Animal models||Xenograft models in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice|
|Formulation||BEZ235 was formulated in 0.9 % NaCl as a homogeneous suspension (9 mg/mL) and stored at 4 °C until further use in the in vivo experiments.|
|Dosages||45 mg/kg body weight, 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||Oncol Rep (2014). Figure 2. BEZ235|
|Cell Lines||OCCC cells|
|Concentrations||10 and 100 nM|
|Incubation Time||72 h|
|Results||OVISE cells were arrested at the G1 phase, but did not exhibit apoptosis (denoted by an increased proportion of cells in sub-G1), after 72 h of treatment with 10 and 100 nM NVP-BEZ235 (Fig. 2A).|
|Source||Oncol Rep (2014). Figure 1. BEZ235|
|Cell Lines||OVISE cells|
|Concentrations||10 and 100 nM|
|Incubation Time||6 or 24 h|
|Results||Treatment with NVP-BEZ235 suppressed pAKT expression, while treatment with temsirolimus did not. Similar results were observed in the KK cells.|
NVP-BEZ235 alone and in combination in mantle cell lymphoma: an effective therapeutic strategy.
Civallero et al. Expert Opin Investig Drugs. 2012 Aug 25. PMID: 22920938.
Dual PI3K/mTOR inhibitor NVP-BEZ235 suppresses hypoxia-inducible factor (HIF)-1α expression by blocking protein translation and increases cell death under hypoxia.
Karar et al. Cancer Biol Ther. 2012 Sep 1;13(11). PMID: 22895065.
Combined PI3K/mTOR and MEK Inhibition Provides Broad Anti-Tumor Activity in Faithful Murine Cancer Models.
Roberts et al. Clin Cancer Res. 2012 Aug 7. PMID: 22872574.
Determination of NVP-BEZ235, a dual PI3K and mTOR inhibitor, in human and mouse plasma and in mouse tissue homogenates by reversed-phase high-performance liquid chromatography with fluorescence detection.
Lin et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jul 15;901:9-17. PMID: 22727754.
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