Chemoprevention of mouse intestinal tumorigenesis by the cyclin-dependent kinase inhibitor SNS-032.
Despite advances in screening and treatment, colorectal cancer remains the second leading cause of cancer-related death in the United States. Cyclin-dependent kinases (Cdk) are deregulated in colorectal cancer by silencing of the Cdk inhibitor p16(Ink4a) and other mechanisms. We tested whether the small molecule Cdk inhibitor SNS-032 (formerly BMS-387032), which targets Cdk2, Cdk7, and Cdk9, can prevent intestinal tumorigenesis in mouse models. We generated mice with high intestinal tumor loads by combining the multiple intestinal neoplasia (Min) mutation with Ink4a/Arf mutations and inducing colitis with dextran sulfate sodium. p16-null Min mice (n = 17) began dextran sulfate sodium treatment at week 5 and i.p. injection of carrier or SNS-032 at week 6. Mice were sacrificed at week 12. SNS-032 was well tolerated and reduced colon tumor burden to 36% of that in carrier-treated mice (P < 0.001). We then extended the study to Ink4/Arf-null Min mice (n = 14) and increased the drug dose frequency. SNS-032 treatment reduced the intestinal tumor number to 25% and intestinal tumor burden to 16% of carrier-treated mice (P < 0.0001). DNA synthesis in non-neoplastic and tumor epithelial cells, detected by bromodeoxyuridine incorporation, was modestly reduced by acute SNS-032 treatment. The mitotic index, detected by histone H3 phosphorylation, was distinctly decreased (P < 0.03), and apoptosis, detected by caspase 3 activation, was increased (P < 0.005). These results show the chemoprevention of intestinal tumorigenesis by SNS-032. Our findings support further study of Cdk inhibitors for chemoprevention and therapy of colon cancer.
Boquoi
Amelie
A
Department of Medicine, Epigenetics and Progenitor Cell Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Chen
Tina
T
Enders
Greg H
GH
D020823:ADP-Ribosylation Factor 1 / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D003092:Colitis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010080:Oxazoles / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*
D019941:Cyclin-Dependent Kinase Inhibitor p16; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases; D020823:ADP-Ribosylation Factor 1