Limits...
Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5.

Exertier P, Javerzat S, Wang B, Franco M, Herbert J, Platonova N, Winandy M, Pujol N, Nivelles O, Ormenese S, Godard V, Becker J, Bicknell R, Pineau R, Wilting J, Bikfalvi A, Hagedorn M - Oncotarget (2013)

Bottom Line: Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro.Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition.In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models.

View Article: PubMed Central - PubMed

Affiliation: University Bordeaux, LAMC, UMR 1029, F-33405 Talence, France.

ABSTRACT
Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.

Show MeSH

Related in: MedlinePlus

Inhibition of Eg5 or KIF20A protein function impairs in vitro angiogenesis in the absence of mitosis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3926828&req=5

Figure 4: Inhibition of Eg5 or KIF20A protein function impairs in vitro angiogenesis in the absence of mitosis

Mentions: Strong perturbation of in vitro angiogenesis was observed after Eg5 blockade using two specific inhibitors, dimethylenastron (DMN; Fig. 4b) and ispinesib (ISP; Fig. 4c and Video 1), whereas solvent-treated cultures were not affected (Fig. 4a and Video 2). Inhibition was observed with ispinesib at both doses (5 and 10 μM). Number of vascular chords was reduced by 2-fold, branching points by nearly 90%, independent chords increased 3-times and number of loops was reduced by 90% (Fig. 4e-h). Less potent inhibition was observed with the Eg5 inhibitor DMN (Fig. 4e-h). Chemical blockade of Mklp2/KIF20A protein using paprotrain also inhibited chord formation (Fig. 4d), albeit at higher doses (20 μM) and to a lesser extent than the KIF11/Eg5 inhibitors (Fig. 4e-h). Mitosis is a very rare event in our assay conditions (Fig. S8). These results demonstrate that kinesin inhibition affects biological processes relevant for angiogenesis, which are distinct from mitosis.


Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5.

Exertier P, Javerzat S, Wang B, Franco M, Herbert J, Platonova N, Winandy M, Pujol N, Nivelles O, Ormenese S, Godard V, Becker J, Bicknell R, Pineau R, Wilting J, Bikfalvi A, Hagedorn M - Oncotarget (2013)

Inhibition of Eg5 or KIF20A protein function impairs in vitro angiogenesis in the absence of mitosis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926828&req=5

Figure 4: Inhibition of Eg5 or KIF20A protein function impairs in vitro angiogenesis in the absence of mitosis
Mentions: Strong perturbation of in vitro angiogenesis was observed after Eg5 blockade using two specific inhibitors, dimethylenastron (DMN; Fig. 4b) and ispinesib (ISP; Fig. 4c and Video 1), whereas solvent-treated cultures were not affected (Fig. 4a and Video 2). Inhibition was observed with ispinesib at both doses (5 and 10 μM). Number of vascular chords was reduced by 2-fold, branching points by nearly 90%, independent chords increased 3-times and number of loops was reduced by 90% (Fig. 4e-h). Less potent inhibition was observed with the Eg5 inhibitor DMN (Fig. 4e-h). Chemical blockade of Mklp2/KIF20A protein using paprotrain also inhibited chord formation (Fig. 4d), albeit at higher doses (20 μM) and to a lesser extent than the KIF11/Eg5 inhibitors (Fig. 4e-h). Mitosis is a very rare event in our assay conditions (Fig. S8). These results demonstrate that kinesin inhibition affects biological processes relevant for angiogenesis, which are distinct from mitosis.

Bottom Line: Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro.Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition.In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models.

View Article: PubMed Central - PubMed

Affiliation: University Bordeaux, LAMC, UMR 1029, F-33405 Talence, France.

ABSTRACT
Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.

Show MeSH
Related in: MedlinePlus