SU11248, a selective tyrosine kinases inhibitor suppresses breast tumor angiogenesis and growth via targeting both tumor vasculature and breast cancer cells

Abstract

SU11248 is a selective inhibitor of certain protein kinases including VEGF receptors. Present study determines whether the anti‐tumor activity of SU11248 results from anti‐angiogenesis, direct anti‐proliferation and anti‐migration effects on breast tumor. Eight wk old female mice (C57BL/6J) were given SU11248 at 20–40 mg/kg/d in drinking water for 4 wks. Control mice received drinking water only. In the 2nd wk, 10^6 E0771 (mouse breast cancer) cells were injected in the left fourth mammary gland. Tumor size was monitored. At the end, tumors were isolated for measuring tumor size and intratumoral microvessel density (IMD) using CD31 immunohistochemistry. SU11248 significantly reduced tumor weight over the control (1.22±0.28 vs. 3.28±0.31 g; n=6; P<0.01) and IMD (111±10 vs. 155±6 IM#/mm^2; P<0.01). Western blot indicated that ERα, VEGF‐R1 and −R2 were expressed in cultured E0771 cells. 3H‐thymidine incorporation showed that SU11248 (10 and 20 μmol/L) significantly suppressed the proliferation of cultured E0771 cells. Migration assay showed that SU11248 (10 μmol/L) significantly inhibited the migration of cultured E0771 cells. These findings support the hypothesis that the anti‐tumor activity of SU11248 on breast cancer is possibly mediated by targeting the paracrine and autocrine effects of VEGF on breast cancer to suppress tumor angiogenesis, proliferation, and migration. (HL51971 & AA013821)