Small molecule inhibition of MDM2-p53 interaction augments radiation response in human tumors
Menée sur des lignées de cellules cancéreuses humaines et à l'aide de xénogreffes, cette étude montre que AMG 232, une petite molécule inhibant l'interaction entre les protéines MDM2 et p53, augmente l'efficacité antitumorale des rayonnements ionisants
MDM2-p53 interaction and downstream signaling impacts cellular response to DNA damage. AMG 232 is a potent small molecule inhibitor that blocks the interaction of MDM2 and p53. We examined the capacity of AMG 232 to augment radiation response across a spectrum of human tumor cell lines and xenografts. AMG 232 effectively inhibited proliferation and enhanced radiosensitivity via inhibition of damage repair signaling. Combined AMG 232 and radiation treatment resulted in the accumulation of
γH2AX-related DNA damage and induction of senescence with promotion of apoptotic and/or autophagic cell death. Several molecules involved in senescence, autophagy and apoptosis were specifically modulated following the combined AMG 232/radiation treatment, including FoxM1, ULK-1, DRAM and BAX. In vivo xenograft studies confirmed more potent anti-tumor and anti-angiogenesis efficacy with combined AMG 232/radiation treatment than treatment with drug or radiation alone. Taken together, these data identify the capacity of AMG 232 to augment radiation response across a variety of tumor types harboring functional p53.
http://mct.aacrjournals.org/content/early/2015/07/10/1535-7163.MCT-14-1056-T.abstract