The VEGF receptors (VEGFRs) mediate signaling leading to angiogenesis, with VEGFR3 (FLT4), activated by VEGF isoforms VEGFC and VEGFD, primarily expressed on lymphatic endothelial cells and directing lymphangiogenesis. MAZ51 is an indolinone that selectively antagonizes the activation of VEGFR3 by VEGFC (IC50 = 1 μM) without blocking VEGFC-mediated stimulation of VEGFR2. It does not inhibit ligand-induced autophosphorylation of EGFR, IGF-1R, or PDGFRβ. By preventing VEGFR3 activation, MAZ51 interferes with an autocrine loop involving the induced expression of the ligand VEGFC as well as VEGFA. It reduces proliferation and induces apoptosis in a variety of cancer cells in vitro and suppresses tumor growth in vivo. MAZ51 is used to study the role of VEGFR3 in endothelial and cancer cell function and survival.
MAZ51 is an indolinone compound that selectively antagonizes the activation of VEGFR-3 by VEGF-C without blocking VEGF-C mediated stumulation of VEGFR-2. This reduces proliferation and induces apoptosis in various cancer cells and suppresses tumor growth.
maz51 caused dramatic shape changes, including the retraction of cellular protrusions and cell rounding in the rat c6 and human u251mg glioma cell lines. maz51 also inhibited cellular proliferation by inducing g2/m phase cell cycle arrest without triggering significant cell death in dose- and time-dependent patterns. treatment of glioma cells with maz51 increased phosphorylated gsk3β levels by activating akt and increasing levels of active rhoa. treatment with maz51 in vegfr-3-silenced cells caused the alterations of cell shape and cytoskeletal arrangements [1]. maz51 surprisingly blocked proliferation of human dermal microvascular endothelial cells (hdmec) with an ic50 of < 1 μm [2].
in the rats subcutaneously injected with mt450 rat mammary carcinoma cells, treatment daily with maz51 (8 mg/kg, i.p.) significantly suppressed the growth of mt450 tumors when compared with the solvent-treated animals [2]. in the mammary fat pad of balb/c mice injected with the metastatic mammary tumor cell line cl66, maz51 treatment (i.p.) significantly inhibited tumor growth in a dose-dependent manner [3].
[1]. park j h, shin y j, riew t r, et al. the indolinone maz51 induces cell rounding and g2/m cell cycle arrest in glioma cells without the inhibition of vegfr-3 phosphorylation: involvement of the rhoa and akt/gsk3β signaling pathways[j]. plos one, 2014, 9(9): e109055.
[2]. kirkin v, thiele w, baumann p, et al. maz51, an indolinone that inhibits endothelial cell and tumor cell growth in vitro, suppresses tumor growth in vivo[j]. international journal of cancer, 2004, 112(6): 986-993.
[3]. michelle l. varney, anguraj sadanandam, joyce c. solheim, james e. talmadge and rakesh k. singh experimental and molecular therapeutics 28: antibodies and therapeutic targets vegfr3 antagonist (maz51) directly and indirectly inhibits murine mammary tumor growth and metastasis.
