Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EGF-receptor family members (EGFRs) as well as c-Src are over expressed in approximately 70% of breast cancer, and in most of the tumors c-Src is co-over expressed with at least one of the EGFRs, suggesting that they may interact functionally and play a role in the development and progression of the malignancy. We hypothesize that a small molecule inhibitor of c-Src dasatinib (BMS-354825; Bristol Myers Squibb), exerts its effects on breast cancer cells by modulating EGFR signaling. Indeed, we found that dasatinib causes inhibition of breast cancer cells overexpressing EGFR, HER-2 and HER-3 (MDA-MB-468, SKBR3, MDA-MB-453, and MDA-MB-231) in a dose and time-dependent manner. Dasatinib also stimulated apoptosis in MDA-MB-468 cells, which could be attributed to activation of both caspase-9 and -8 and arrest of the cell cycle at G0/G1 cycle. Furthermore, dasatinib markedly inhibited colony formation, cell invasion, migration and angiogenesis, accompanied by decreased phosphorylation of EGFR and c-Src and their downstream effector molecules Akt and Erks. Our data suggest that dasatinib mediates its action in part through EGFR signaling and could be a potential therapeutic agent for breast cancer.
 ...
PMID:Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. 1939 50

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.
 ...
PMID:Dasatinib reduces 5-Fu-triggered apoptosis in colon carcinoma by directly modulating Src-dependent caspase-9 phosphorylation. 2984 31