体外研究
(In Vitro) | Neratinib displays no activity against other serine-threonine kinases such as Akt, cyclin D1/cdk4, cyclin E/cdk2, cyclin B1/cdk1, IKK-2, MK-2, PDK1, c-Raf, and Tpl-2, as well as the tyrosine kinase c-Met[1].
Neratinib (0.5 ng/mL–5 μg/mL, 2 days) inhibits the proliferation of cell lines that show high levels of HER-2 (3T3/neu, SK-Br-3, and BT474) and is much less active in cell lines that express neither HER-2 nor EGFR (3T3, MDA-MB-435, and SW620)[1].
Neratinib (0-2 nM, 12-16 h) arrests BT474 cell cycle at G1-S phase[1].
Neratinib results in the inhibition of MAPK and Akt phosphorylation, down-regulation of cyclin D1 levels, and induction of p27[1].
Cell Proliferation Assay[1] | Cell Line: | 3T3, 3T3/neu, SK-Br-3, BT 474, A431, MDA-MB-435 and SW620 | | Concentration: | 0.5 ng/mL–5 μg/mL | | Incubation Time: | 2 days (6 days for BT474) | | Result: | Inhibited cell proliferation with IC50values of 700 ± 78, 3 ± 0.14, 2 ± 0.18, 2 ± 0.06, 81± 9, 960 ± 165 and 690 ± 84 nM against 3T3, 3T3/neu, SK-Br-3, BT 474, A431, MDA-MB-435 and SW620 cells, respectively. |
Western Blot Analysis[1] | Cell Line: | BT474 or A431 cells | | Concentration: | 0, 2, 10, 50, 100 and 200 nM | | Incubation Time: | 3 h | | Result: | Decreased ligand-independent receptor phosphorylation by 50% (IC50) at 5 nM in BT474 cells, repressed EGF-dependent phosphorylation of EGFR in A431 cells at a comparable dose (IC50= 3 nM).
Effectively repressed phosphorylation of MAPK and Akt in BT474 cells. |
Cell Cycle Analysis[1] | Cell Line: | BT474 | | Concentration: | 0–2 nM | | Incubation Time: | 12–16 h | | Result: | Blocked cell cycle progression, causing a G1-S arrest, a 50% decrease in the number of cells in the S (DNA synthesis) phase of the cell cycle was observed at a concentration of 2 nM. |
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体内研究
(In Vivo) | Neratinib (HKI-272) (0-80 mg/kg/day; i.g.; 42 days) shows anticancer activities against cancer cells that expresses high levels of HER-2 or EGFR[1].
| Animal Model: | Female athymic (nude) mice, tumor xenograft[1] | | Dosage: | 10, 20, 40, 60 or 80 mg/kg/day | | Administration: | Gavage, 42 days | | Result: | Reduced tumor growth in a dose-dependent manner in 3T3/neu, BT474, SK-OV-3 and A431 xenografts, but was o inactive in xenografts of MX-1 and MCF-7. Inhibited phosphorylation of HER-2 in BT474 xenografts. |
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