Integrin-linked kinase (ILK) mediates the phosphorylation of multiple signaling proteins, such as Akt at Ser-473, GSK3β and myosin light chain. ILK-IN-2 is an ILK inhibitor with an IC50 value of 0.6 μM. It showed high anti-proliferative potency in a panel of prostate and breast cancer cell lines with IC50 values ranging from 1 – 2.5 μM. On the contrary, the viability of normal prostate epithelial cells and mammary epithelial cells was not affected by ILK-IN-2 at the doses of 1 – 5 μM. In PC-3 and SKBR3 cell lines, ILK-IN-2 dose-dependently downregulated the expressions of YB-1, HER2, and EGFR at both protein and transcript levels. The overexpression of constitutively active-ILK, however, diminished the suppressive effect of ILK-IN-2 on these signaling effectors. ILK-IN-2 at 1 – 4 μM exhibited dose-dependent inhibitory effects on the phosphorylation of ERK1/2 and p38, but not JNK. Moreover, ILK-IN-2 at 1 – 4 μM induced apoptosis and autophagy in PC-3 cells after 24h of treatment. In an ectopic PC-3 tumor xenograft model, oral treatment of ILK-IN-2 (25 and 50 mg/kg, once daily) for 35 days significantly suppressed tumor growth relative to vehicle-treated controls. A dose-dependent inhibition of the phosphorylation of Ser-473-Akt, GSK3β and MLC was also observed in ILK-IN-2-treated mice[2].
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