| Reference | 1. PLoS One. 2014 Sep 30;9(9):e109055. doi: 10.1371/journal.pone.0109055.
eCollection 2014. <br />
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. <br />
Park JH(1), Shin YJ(1), Riew TR(1), Lee MY(1). <br />
Author information: <br />
(1)Department of Anatomy, Catholic Neuroscience Institute, College of Medicine,
The Catholic University of Korea, Seoul, Korea. <br />
MAZ51 is an indolinone-based molecule originally synthesized as a selective
inhibitor of vascular endothelial growth factor receptor (VEGFR)-3 tyrosine
kinase. This study shows that exposure of two glioma cell lines, rat C6 and human
U251MG, to MAZ51 caused dramatic shape changes, including the retraction of
cellular protrusions and cell rounding. These changes were caused by the
clustering and aggregation of actin filaments and microtubules. MAZ51 also
induced G2/M phase cell cycle arrest. This led to an inhibition of cellular
proliferation, without triggering significant cell death. These alterations
induced by MAZ51 occurred with similar dose- and time-dependent patterns.
Treatment of glioma cells with MAZ51 resulted in increased levels of
phosphorylated GSK3β through the activation of Akt, as well as increased levels
of active RhoA. Interestingly, MAZ51 did not affect the morphology and cell cycle
patterns of rat primary cortical astrocytes, suggesting it selectively targeted
transformed cells. Immunoprecipitation-western blot analyses indicated that MAZ51
did not decrease, but rather increased, tyrosine phosphorylation of VEGFR-3. To
confirm this unanticipated result, several additional experiments were conducted.
Enhancing VEGFR-3 phosphorylation by treatment of glioma cells with VEGF-C
affected neither cytoskeleton arrangements nor cell cycle patterns. In addition,
the knockdown of VEGFR-3 in glioma cells did not cause morphological or
cytoskeletal alterations. Furthermore, treatment of VEGFR-3-silenced cells with
MAZ51 caused the same alterations of cell shape and cytoskeletal arrangements as
that observed in control cells. These data indicate that MAZ51 causes
cytoskeletal alterations and G2/M cell cycle arrest in glioma cells. These
effects are mediated through phosphorylation of Akt/GSK3β and activation of RhoA.
The anti-proliferative activity of MAZ51 does not require the inhibition of
VEGFR-3 phosphorylation, suggesting that it is a potential candidate for further
clinical investigation for treatment of gliomas, although the precise
mechanism(s) underlying its effects remain to be determined. <br />
2. Int J Cancer. 2004 Dec 20;112(6):986-93. <br />
MAZ51, an indolinone that inhibits endothelial cell and tumor cell growth in
vitro, suppresses tumor growth in vivo. <br />
Kirkin V(1), Thiele W, Baumann P, Mazitschek R, Rohde K, Fellbrich G, Weich H,
Waltenberger J, Giannis A, Sleeman JP. <br />
Author information: <br />
(1)Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, Karlsruhe,
Germany. <br />
We have recently described MAZ51, an indolinone that blocks the ligand-induced
autophosphorylation of VEGFR-3, a receptor tyrosine kinase that plays a central
role in the regulation of lymphangiogenesis. Here we show that MAZ51 is able to
block the proliferation of VEGFR-3-expressing human endothelial cells and is less
potently able to induce their apoptosis. MAZ51 also inhibits the proliferation
and induces the apoptosis of a variety of non-VEGFR-3-expressing tumor cell
lines. These data suggest that MAZ51 blocks the activity of tyrosine kinases in
addition to VEGFR-3. In vivo, MAZ51 significantly inhibits the growth of rat
mammary carcinomas. These data establish MAZ51 as a compound with antitumor
properties that inhibits tumor growth directly and also indirectly by interfering
with tumor-host interactions. <br />
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