Calpain-2 抑制剂治疗优先减少表达最高水平这种酶的人结肠癌细胞的肿瘤进展。,Cancer Medicine

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Calpain-2 抑制剂治疗优先减少表达最高水平这种酶的人结肠癌细胞的肿瘤进展。
Cancer Medicine ( IF 2.9 ) Pub Date : 2017-12-06 , DOI: 10.1002/cam4.1260
Michael P Marciel ₁ , Aaron H Rose ₁ , Verena Martinez ₂ , David T Horio ₃ , Ann S Hashimoto ₁ , FuKun W Hoffmann ₁ , Pietro Bertino ₁ , Peter R Hoffmann ₁

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Calpain-2 水平在对化疗耐药的结直肠肿瘤中较高，之前的研究表明，calpain-2 抑制剂治疗可减少炎症驱动的结直肠癌，但并未证实该抑制剂对结肠癌细胞本身的直接作用。在本研究中，5 种人结肠癌细胞系直接用 calpain-2 抑制剂处理，结果显示 5 种细胞系中有 4 种细胞死亡增加，所有 5 种细胞系的锚定非依赖性生长减少。当测试 calpain-2 的水平时，三种细胞系表现出这种酶的水平升高：HCT15（低）、HCC2998（中）和 HCT116（显着更高）。这与凝胶移位测定一致，表明 calpain-2 抑制剂在 HCT116 细胞中最有效地减少了 NF-κB 核转位。使用这三种细胞系的荧光素酶表达细胞的直肠内移植来评估 calpain-2 抑制剂在体内阻碍肿瘤进展的能力。结果表明，仅在注射了 HCT116 细胞的小鼠中，calpain-2 抑制剂治疗减少了肿瘤生长并增加了存活率。这些数据表明 calpain-2 抑制剂治疗可能对表达最高水平 calpain-2 的结肠直肠肿瘤最有效。

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Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme.

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.

更新日期：2017-12-15

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