4.6 Article

Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation

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CELL DEATH DISCOVERY
卷 4, 期 -, 页码 -

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SPRINGERNATURE
DOI: 10.1038/s41420-018-0062-5

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资金

  1. Chinese National Natural Science Foundation [81401944, 81472602, 81602154, 81672936, 81672739]
  2. Henan Health Department [201401004]
  3. Technology Research Projects of Henan Science and Technology Department [142300410378, 162102410060, 182107000054]
  4. Key Scientific Research Projects of Colleges and Universities of Henan Province Department of Education [15A320014]
  5. Special Funding for Doctoral Team of the First Affiliated Hospital of Zhengzhou University [2016-BSTDJJ-11]

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Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. Dasatinib dramatically decreased 5-Fu triggered apoptosis in colon carcinoma via suppression of Src activation. Our findings may have partially explained why dasatinib combined with FOLFOX failed to show a meaningful clinical response in mCRC.

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