Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy.
The involvement of alpha(v)beta3 and alpha(v)beta5 integrins in angiogenesis and the use of integrin antagonists as effective antiangiogenic agents are documented. Radiotherapy is an important therapy option for cancer. It has been shown that ionizing radiation exerts primarily antiangiogenic effects in tumors but has also proangiogenic effects as the reaction of the tumor to protect its own vasculature from radiation damage. Here, we show that combined treatment with S247, an Arg-Gly-Glu peptidomimetic antagonist of alpha(v)beta3 integrin, and external beam radiotherapy are beneficial in local tumor therapy. We found that radiation up-regulates alpha(v)beta3 expression in endothelial cells and consecutively phosphorylates Akt, which may provide a tumor escape mechanism from radiation injury mediated by integrin survival signaling. In the presence of S247, the radiation-induced Akt phosphorylation is strongly inhibited. Our studies on endothelial cell proliferation, migration, tube formation, apoptosis, and clonogenic survival show that the radiosensitivity of endothelial cells is enhanced by the concurrent administration of the integrin antagonist. The in vitro data are successfully translated into human glioma (U87), epidermoid (A431), and prostate cancer (PC3) xenograft models growing s.c. on BALB/c-nu/nu mice. In vivo, the combination of S247 treatment and fractionated radiotherapy (5 x 2.5 Gy) leads to enhanced antiangiogenic and antitumor effects compared with either monotherapies. These results underline the importance of alpha(v)beta3 integrin when tumors protect their microvasculature from radiation-induced damage. The data also indicate that the combination of integrin antagonists and radiotherapy represents a rational approach in local cancer therapy.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany.
Griggs
David W
DW
Zieher
Heike
H
Roth
Alexandra
A
Lipson
Kenneth E
KE
Saffrich
Rainer
R
Gröne
Hermann-Josef
HJ
Hallahan
Dennis E
DE
Reisfeld
Ralph A
RA
Debus
Juergen
J
Niethammer
Andreas G
AG
Huber
Peter E
PE
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000378:metabolism / Q000528:radiation effects; D005910:Glioma / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009930:Organic Chemicals / Q000627:therapeutic use*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009930:Organic Chemicals; D011518:Proto-Oncogene Proteins; C474314:S 247 compound; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt