AG-1024 is a selective IGF-1R inhibitor with an IC50 of 0.4 μM. Exposure to Tyrphostin AG 1024 inhibits proliferation of cell and triggers their apoptosis in a time-dependent manner. Tyrphostin AG 1024 prevents the growth inhibition for IC20 plus irradiation (4 Gy) by 50% compared to the control.Examination of Tyrphostin AG 1024 effects on radiation response demonstrates a marked enhancement in radiosensitivity and amplification of radiation-induced apoptosis. Tyrphostin AG 1024-induced apoptosis is associated with a downregulation of expression of phospho-Akt1, increased expression of Bax, p53 and p21, and a decreased expression of bcl-2 expression, especially when combined with irradiation. Tyrphostin AG 1024 is an effective anti-proliferative agent for breast carcinoma cells MCF-7. IGF1-R inhibitor tyrphostin AG1024 (10 μm) restores H358 cells apoptosis when cultured in serum-free medium. Incubation with AG1024 markedly decreases the AR level detected in the serum-free culture medium. AG1024 reduces IGF1 release in the serum-free culture medium. AG1024 enhances the apoptosis-inducing effect of gefitinib.Tyrphostin AG1024 significantly inhibits signal transmission by Akt (PKB), ERK (1/2), Src and STAT.The cytotoxic effect of AG1024 is more than 100 times greater on nutrient-deprived PANC-1 cells (NDM) with an IC50 of 55 nM, relative to cells in nutrient-sufficient medium (DMEM) with an IC50 of 21 μM. In DMEM, 0.3 μM AG1024 does not induce any significant PANC-1 cell death as determined using propidium iodide and annexin V staining and flow cytometry. In contrast, 34% of the cells grown in NDM and treated with the same concentration of AG1024 reveals propidium iodide-positive/annexin V-negative staining. In addition, AG1024 gives rise to significant increases in neuronal ADDL binding both when AG1024 is added alone and in the presence of exogenous insulin.
|Source||Oncotarget (2016). Figure 3. AG-1024|
|Method||IGF-1R signaling analyses|
|Cell Lines||NSCLC U-1810 cells|
|Incubation Time||24 hours|
|Results||Interestingly, when cells were exposed to AG1024, a kinase inhibitor of IGF-1R at an IC50- dose IGF-1R β signals still remained illustrating that this TKI is not completely depleting IGF-1R β from the cells|
|Preparation method||Cells are exposed to AG-1024 for 24, 48 or 72 hours. For the determination of proliferation, cells are harvested and counted with trypan blue dye exclusion. Apoptosis is evaluated by dual staining of MCF-7 with fluoresceine anti-digoxigenin and propidium iodide. Briefly, fixed cells are washed with PBS, suspended in TdT buffer with TdT enzyme and Dig-dUTP for 60 minutes, and suspended in FITC blocking solution with anti-Dig-Fluorescein for 30 minutes at room temperature and kept in a dark place. Cells are then rinsed in buffer and resuspended in propidium iodide/RNase A solution for 30 minutes then analyzed by flow cytometry. For the assessment of phospho-Akt1, Bax, p53, bcl-2 and p21, cells are lysed and analyzed by western blot.|
|Concentrations||Dissolved in DMSO, final concentration 10 μM|
|Incubation time||24, 48 or 72 hours|
|Animal models||Female nude mice implanted subcutaneously with Ba/F3-p210 cells|
|Formulation||Dissolved in DMSO, and diluted in PBS|
|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 55 mg/mL|
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