AS703026 is a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs).
|Cell lines||MM cell lines|
|Preparation method||Cytotoxicity assays.
The inhibitory effects of study compounds on MM cell growth and survival were assessed by both [3H]thymidine incorporation and by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Sigma-Aldrich, St Louis, MO) dye absorbance following the manufacturer's instruction. Cells (104/well for MM cell line, in triplicates and 2-5×105/well for patient MM cells) were cultured in 96-well plates for 3 days (MM cell lines) or 5-days (patient MM cells). For the [3H]thymidine incorporation assay, cells were pulsed with 0.5 μCi (0.0185 MBq)/well [3H]thymidine (Amersham, Pittsburgh, PA) for 6 h (cell lines), harvested onto glass fiber filters, and counted in a β-scintillation counter. Due to low DNA synthesis of patient MM cells, they were pulsed with 2 μCi/well [3H]thymidine and measured during the last 36 h of culture.
|Concentrations||0, 2, 20, 200, 2000, 20000 nM|
|Incubation time||3 days|
|Animal models||H929 cells human plasmacytoma xenograft model|
|Formulation||suspended in 0.5% carboxymethylcellulose (CMC)/0.25%Tween20 at 10 mg/ml|
|Dosages||15 or 30 mg/kg 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.
MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy.
Yoon et al. Cancer Res. 2011 Jan 15;71(2):445-53. PMID: 21118963.
Blockade of the MEK/ERK signaling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo.
Kihyun et al. Br J Haematol. 2010 May;149(4): 537–549. PMID: 20331454.
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