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 VEGFR types 1-3 that are expressed in human breast cancer. The present study determines whether the anti-tumor activity of SU11248 results from the inhibition of angiogenesis, as well as direct anti-proliferation and anti-migration effects on breast tumors. Eight-wk old female mice (C57BL/6) were given SU11248 at 20-40 mg/kg/d in drinking (distilled) 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 using dial calipers. 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 = 8; p < 0.01) and IMD (111 ± 10 vs. 155 ± 6 IM#/mm2; p < 0.01). RT-PCR indicated that VEGFR1 and R2 were expressed in cultured E0771 cells. VEGF (10 ng/ml) caused a 42% increase in proliferation of E0771 cells, compared to the control (p < 0.01; n = 8), and there was a significant decrease in proliferation of E0771 cells treated with VEGF plus SU11248 (10 μmol/L) vs. the control (65%, p < 0.01). VEGF caused a 2-fold increase in the proliferation of HUVEC vs. the control (p < 0.01; n = 8), but its action was completely eradicated by SU11248. Neither VEGF nor SU11248 had any effect on the proliferation of cultured HAS MC. Migration assay showed that SU11248 (10 μmol/L) significantly inhibited the migration of cultured E0771 cells. SU11248 significantly inhibited the proliferation of MCF-7 and MDAMB-231 cells in a dose-related manner. These findings support the hypothesis that the antitumor 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.

Sunitinib enhances antitumor effects against chemotherapy-resistant bladder cancer through suppression of ERK1/2 phosphorylation

“…The antitumor activity of sunitinib has been shown in preclinical and clinical studies (7,18). Tumor regression has been shown in different xenograft models of colon cancer, breast cancer, non-small cell lung cancer, melanoma, glioblastoma and renal carcinoma (18,(29)(30)(31)(32)(33). Sunitinib clearly inhibited cell proliferation in vitro and tumor growth in vivo in the present study (Figs.…”

Monomeric gremlin is a novel vascular endothelial growth factor receptor-2 antagonist

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“…Using E0771 (mouse breast cancer) cells in C57BL/6 mice, we have recently reported that VEGF and its receptors are the important biological markers for breast cancer malignancy and progression, and demonstrated that the paracrine effects (especially angiogenesis) and the autocrine effects (proliferation and migration) of VEGF are involved in promoting breast cancer progression. 14 Thus, enhanced VEGF expression and angiogenesis in obesity contribute to breast cancer progression.…”