Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells

Nam, Sangkil; Kim, Donghwa; Cheng, Jin Q.; Zhang, Shumin; Lee, Ji‐Hyun; Buettner, Ralf; Mirosevich, Janni; Lee, Francis Y.; Jove, Richard

doi:10.1158/0008-5472.can-05-1731

Cited by 341 publications

(295 citation statements)

References 19 publications

Supporting

Mentioning

282

Contrasting

Order By: Relevance

“…We also showed that dasatinib directly inhibits the kinase activities of Src and other SFKs in human prostate cancer cells both in vitro and in vivo (20). To examine the effects of dasatinib on autophosphorylation levels of Src and other SFKs in CML cells, Western blot analyses were done.…”

Section: Results and Discussion Dasatinib Inhibits Tyrosyl Phosphorylmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Nam¹,

Williams

Vultur³

et al. 2007

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Dasatinib (BMS-354825) is a novel, oral, potent, multitargeted kinase inhibitor of Bcr-Abl and Src family kinases (SFK) and is a promising cancer therapeutic agent. Preclinical data indicate that dasatinib is 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl, and that dasatinib is active against 18 of 19 Bcr-Abl mutations known to cause imatinib resistance. Phase I clinical data show that dasatinib is well tolerated and highly effective for the treatment of imatinib-resistant/ imatinib-intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome -positive acute lymphoblastic leukemia. However, the molecular mechanism of action of dasatinib is not fully understood. In this study, we confirm that dasatinib inhibits tyrosine phosphorylation of SFKs, including Src, Hck, and Lyn, in K562 human CML cells. Significantly, downstream signal transducer and activator of transcription 5 (Stat5) signaling is also blocked by dasatinib as shown by decreases in levels of phosphorylated Stat5 and Stat5 DNA-binding activities. In addition, dasatinib down-regulates expression of Stat5 target genes, including Bcl-x, Mcl-1, and cyclin D1. Consistent with these results, blockade of Stat5 signaling by dasatinib is accompanied by inhibition of cell proliferation and induction of apoptosis. Surprisingly, Stat5 DNA-binding activities are enhanced with increasing cell density, which is associated with resistance to apoptosis by dasatinib. Our findings indicate that inhibition of Stat5 signaling downstream of Bcr-Abl/SFKs contributes to the action of dasatinib, and, conversely, that increasing cell density up-regulates Stat5 activation and confers resistance to dasatinib. Moreover, the level of phosphorylated Stat5 in CML cells represents a mechanistically relevant biomarker for monitoring inhibition of Bcr-Abl signaling by dasatinib in CML patients using convenient immunocytochemical assays.

show abstract

Section: Results and Discussion Dasatinib Inhibits Tyrosyl Phosphorylmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Nam¹,

Williams

Vultur³

et al. 2007

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that dasatinib inhibits proliferation of LNCaP, PC-3 and DU-145 CaP cells in vitro (Lombardo et al, 2004;Nam et al, 2005). The effects of dasatinib on C4-2B have not been previously evaluated, and therefore, we first examined the effects of dasatinib on these cells in vitro.…”

Section: In Vitro Effects Of Dasatinib On C4-2b Cellsmentioning

confidence: 99%

“…Recently, dasatinib has been shown to inhibit proliferation, cell adhesion, migration and invasion of CaP cells in vitro (Lombardo et al, 2004;Nam et al, 2005). Furthermore, dasatinib decreased the growth of PC-3 CaP cells injected orthotopically, reduced the number of metastases and inhibited growth at the metastatic site (Park et al, 2008;Yano et al, 2008).…”

mentioning

confidence: 99%

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone. METHODS: C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed. RESULTS: Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3 ± 0.4 vs 9.2 ± 2.1 (P ¼ 0.004). Combination therapy improved efficacy over dasatinib alone (P ¼ 0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (Po0.001). CONCLUSION: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.

show abstract

“…76 The clinical relevance of Src and Abl is evidenced by several pharmacological kinase inhibitors currently used as chemotherapeutic medicines. [77][78][79][80] As shown in Figure 1, Src and Abl are both myristoylated, which drives them to the plasma membrane. 74,76,81 Src and Abl both contain an SH3, SH2, and catalytic (SH1) domain in similar orientation.…”

Section: Monographsmentioning

confidence: 99%

Src Points the Way to Biomarkers and Chemotherapeutic Targets

Krishnan¹,

Miller

Goldberg³

2012

Genes & Cancer

View full text Add to dashboard Cite

The role of Src in tumorigenesis has been extensively studied since the work of Peyton Rous over a hundred years ago. Src is a non-receptor tyrosine kinase that plays key roles in signaling pathways controlling tumor cell growth and migration. Src regulates the activities of numerous molecules to induce cell transformation. However, transformed cells do not always migrate and realize their tumorigenic potential. They can be normalized by surrounding nontransformed cells by a process called contact normalization. Tumor cells need to override contact normalization to become malignant or metastatic. In this review, we discuss the role of Src in cell migration and contact normalization, with emphasis on Cas and Abl pathways. This paradigm illuminates several chemotherapeutic targets and may lead to the identification of new biomarkers and the development of effective anticancer treatments.

show abstract

Action of the Src Family Kinase Inhibitor, Dasatinib (BMS-354825), on Human Prostate Cancer Cells

Cited by 341 publications

References 19 publications

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Src Points the Way to Biomarkers and Chemotherapeutic Targets

Contact Info

Product

Resources

About