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.