Chemoprevention of mouse intestinal tumorigenesis by the cyclin-dependent kinase inhibitor SNS-032.
Chemoprevention of mouse intestinal tumorigenesis by the cyclin-dependent kinase inhibitor SNS-032.
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DOI：
10.1158/1940-6207.capr-09-0053
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Enders GH
中科院分区：
文献类型：
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作者：
Boquoi A;Chen T;Enders GH
尽管筛查和治疗取得了进步，结直肠癌（CRC）仍然是美国癌症相关死亡的第二大原因。通过 Cdk 抑制剂 p16Ink4a 的沉默和其他机制，细胞周期蛋白依赖性激酶 (Cdks) 在 CRC 中失调。我们测试了针对 Cdks 2、7 和 9 的小分子 Cdk 抑制剂 SNS-032（以前称为 BMS-387032）是否可以预防小鼠模型中的肠道肿瘤发生。我们通过将 Min（多发性肠道肿瘤）突变与 Ink4a/Arf 突变相结合，并用葡聚糖硫酸钠 (DSS) 诱导结肠炎，产生了具有高肠道肿瘤负荷的小鼠。 p16 缺失 Min 小鼠 (N = 17) 在第 5 周开始 DSS 治疗，并在第 6 周腹腔注射载体或 SNS-032。在第 12 周处死小鼠。SNS-032 耐受性良好，并将结肠肿瘤负荷降低至载体治疗小鼠的 36% (P < 0.001)。然后我们将研究扩展到 Ink4/Arf-null Min 小鼠 (N = 14) 并增加药物剂量频率。载体治疗小鼠的 SNS-032 治疗将肠道肿瘤数量减少至 25%，肠道肿瘤负荷减少至 16%（P < 0.0001）。通过溴脱氧尿苷掺入检测，非肿瘤和肿瘤上皮细胞中的 DNA 合成因 SNS-032 急性治疗而略有减少。通过组蛋白 H3 磷酸化检测到的有丝分裂指数明显降低（P < 0.03），通过 caspase 3 激活检测到的细胞凋亡增加（P < 0.005）。这些结果证明 SNS-032 对肠道肿瘤发生具有化学预防作用。我们的研究结果支持进一步研究 Cdk 抑制剂用于结肠癌的化学预防和治疗。
Despite advances in screening and treatment, colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States. Cyclin-dependent kinases (Cdks) are deregulated in CRC by silencing of the Cdk inhibitor p16Ink4a and other mechanisms. We tested whether the small molecule Cdk inhibitor SNS-032 (formerly BMS-387032), which targets Cdks 2, 7, and 9, can prevent intestinal tumorigenesis in mouse models. We generated mice with high intestinal tumor loads by combining the Min (Multiple intestinal neoplasia) mutation with Ink4a/Arf mutations and inducing colitis with dextran sulfate sodium (DSS). p16-null Min mice (N = 17) began DSS treatment at week 5 and intraperitoneal 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 demonstrate chemoprevention of intestinal tumorigenesis by SNS-032. Our findings support further study of Cdk inhibitors for chemoprevention and therapy of colon cancer.