TAE226-mediated inhibition of focal adhesion kinase interferes with tumor angiogenesis and vasculogenesis.
Neoangiogenesis plays an important role in tumor growth and metastasis. Evaluation of new anti-angiogenic targets may broaden the armament for future therapeutic concepts. Focal adhesion kinase (FAK), expressed in endothelial and tumor cells, is essential for adhesion and mobility of adherent cells. In the current study we analyzed the anti-angiogenic properties of the FAK inhibitor TAE226 on the proliferation of blood outgrowth endothelial cell (OEC) and differentiation of endothelial progenitor cells (EPC), derived from peripheral blood CD133(+) cells, tube formation and on neovascularization in a HT29 xenotransplant model. The effects of TAE226 were compared to those of the rapamycin analogue RAD001. The combination of both drugs was also studied. We showed that HT29 tumor cells and OEC were most sensitive to the action of TAE226 compared to EPC in vitro. In contrast, RAD001 affected the proliferation of both types of endothelial cells stronger than that of HT29 cells. Furthermore we could show that TAE226 inhibited tube formation in a dose dependent manner. In a HT29 subcutaneous tumor model TAE226 and RAD001 diminished MVD at commonly employed doses to a similar degree. Combination of both compounds did not show synergy in vitro or in vivo. Since TAE226 has been shown to inhibit the PI3 kinase, Akt kinase, mTor pathway, addition of RAD001 may not increase this effect. In conclusion, we have shown that treatment with TAE leads to a reduction of neoangiogenesis in vitro and in a mouse model. The effects are mediated by inhibition of angiogenesis and vasculogenic OEC and EPC.
University Medical Center Hamburg-Eppendorf, Hubertus Wald University Cancer Center Hamburg, Dept. of Oncology/Hematology with sections BMT and Pneumology, Hamburg, Germany.
Alexander
A
Schultze
Sebastian
S
Decker
Jasmin
J
Otten
Andrea Kristina
AK
Horst
Gabi
G
Vohwinkel
Gunter
G
Schuch
Carsten
C
Bokemeyer
Sonja
S
Loges
Walter
W
Fiedler
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000068338:Everolimus; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D038081:Organogenesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D009025:Morpholines; D047428:Protein Kinase Inhibitors; C524632:TAE226; D000068338:Everolimus; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020123:Sirolimus