title: Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.
abstract: Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration. PD treatment also enhanced LGR5+ stem cell survival and regeneration after radiation. PD was an on-target inhibitor of RB phosphorylation and blocked G1/S transition in the intestinal crypts. PD treatment strongly but reversibly inhibited radiation-induced p53 activation, which blocked p53-upregulated modulator of apoptosis-dependent (PUMA-dependent) apoptosis without affecting p21-dependent suppression of DNA damage accumulation, with a repair bias toward nonhomologous end joining. Further, deletion of PUMA synergized with PD treatment for even greater intestinal radioprotection. Our results demonstrate that the cell cycle critically regulates the DNA damage response and survival of intestinal stem cells and support the concept that pharmacological quiescence is a potentially highly effective and selective strategy for intestinal radioprotection.
authors.forename: Liang
authors.initials: L
authors.lastname: Wei
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Leibowitz
authors.forename: Xinwei
authors.initials: X
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Epperly
authors.forename: Joel
authors.initials: J
authors.lastname: Greenberger
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology; D004249:DNA Damage / Q000235:genetics / Q000276:immunology; D007410:Intestinal Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000276:immunology* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C493597:Lgr5 protein, mouse; C488588:PUMA protein, mouse; D010879:Piperazines; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib