Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate–resistant Bcr-Abl kinases

Warmuth, Markus; Simon, N.; Mitina, Olga; Mathes, Ruth; Fabbro, Doriano; Manley, Paul W.; Buchdunger, Elisabeth; Forster, Karin; Moarefi, Ismail; Hallek, Michael

doi:10.1182/blood-2002-01-0288

Cited by 127 publications

(89 citation statements)

References 27 publications

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“…Interestingly, this interaction does not require the phosphorylation of the partners (Klejman et al, 2002) and our unpublished data also argue for a constitutive Stat5/Hck interaction in Ba/F3 cells expressing Tel-Abl that does not require the phosphorylation of Stat5 or Hck. However, since treatment with imatinib mesylate or PP2 which has been reported to inhibit also Bcr-Abl (Tatton et al, 2003;Warmuth et al, 2003) and herein Tel-Abl, suppresses Stat5 phosphorylation, Tel-Abl itself or another Src kinase may activate these factors. Although the Lyn kinase was shown to physically interact with and activate Stat5 factors (Danhauser-Riedl et al, 1996;Chin et al, 1998;Tilbrook et al, 2001), the absence of any effect of the dominant-negative form of the kinase on Stat5 phosphorylation in Tel-Abl-expressing cells do not argue for a role of Lyn in this process (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

et al. 2006

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Section: Discussionmentioning

confidence: 99%

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

et al. 2006

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“…102,103 In mouse studies, CGP76030 impaired osteoclast bone resorption and decreased the incidence of bone and visceral metastases. 25 Both agents demonstrated in vitro effects on osteoclasts and in vivo effects on experimentally induced bone loss.…”

Section: Angiogenesismentioning

confidence: 99%

“…25,102 AP22408 and AP23451 are bone-targeted Src inhibitors that inhibit tyrosine kinase activity. AP22408 has demonstrated antiosteoclast and antiresorptive Dasatinib (BMS-354825) [79][80][81][82][83][84][85][86] Src, Lyn, Bcr-Abl, c-kit, PDGFR, ephrin AZD-0530 [87][88][89][90][91][92][93][94][95][96] Src, Bcr-Abl Bosutinib (SKI-606) [97][98][99] Src, Bcr-Abl XL999 100,101 Src, VEGFR2, c-kit, PDGFR, FGFR1 CGP77675 25,102 Src, Lck, Yes, EGFR, VEGFR, FAK CGP76030 103 Src, Lck, Yes, Bcr-Abl AP22408 104 Src AP23451 105 Src UCS15A 106 Src AP22161 107 Src S1 peptide 108 Src/androgen receptor interaction activity in vitro and in vivo. 104 AP23451 prevented osteolytic lesions in mice inoculated with a human breast cancer cell line.…”

Section: Angiogenesismentioning

confidence: 99%

Targeting Src signaling in metastatic bone disease

Araujo¹,

Logothetis²

2008

Intl Journal of Cancer

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Src is a tyrosine kinase involved in the regulation of a range of cellular processes including proliferation, adhesion, motility and survival. In addition, it is a key regulator of bone metabolism. Src has been implicated in the pathogenesis of a number of cancers, and has been found to be overexpressed in breast, prostate, colorectal, pancreatic and nonsmall-cell lung tumors. There is also evidence that aberrant Src signaling may contribute to the increased osteoclastic activity associated with bone metastases. Bone metastases frequently occur in cancer patients with advanced disease. The metastasized cells disrupt normal bone remodeling pathways resulting in the release of growth factors that further promote tumor growth. Thus, a cycle of metastatic bone destruction is initiated, leading to compromised skeletal integrity and substantially reduced quality of life. Because of the role of Src in both cancer development and in bone metabolism, it may provide a therapeutic target for patients with bone metastases. ' 2008 Wiley-Liss, Inc.Key words: Src signaling; tyrosine kinase; bone metastases; osteoclasts Bone involvement in advanced cancerBone metastases are common in several cancers, including breast, prostate, colorectal and lung cancer. In addition, nearly all patients with multiple myeloma experience bone lesions. 1 Although bone resorption by osteoclasts and synthesis of new bone by osteoblasts is tightly regulated in normal bone metabolism, malignant cells dysregulate the bone remodeling process. The chronic presence of bone metastases often results in complete pathologic remodeling of the affected bone compartment.If untreated, bone metastases lead to skeletal complications such as fractures, spinal cord compression and bone pain, all of which may profoundly reduce patients' quality of life. Therefore, early diagnosis and adequate treatment of bone metastases is critically important.Cancer patients are also at risk of bone loss as a result of certain cancer therapies. In premenopausal women, chemotherapy can cause ovarian failure, leading to early menopause and rapid bone loss. 2 Adjuvant endocrine therapies that deplete peripheral sex hormone production can also reduce bone mass. Bone loss is also frequently seen in men receiving androgen-deprivation therapy for prostate cancer, leading to an increased risk of osteoporotic fracture. 3 Molecular biology of Src family kinasesSrc (encoded by the c-src gene) is a nonreceptor tyrosine kinase localized to the cellular membrane, involved in the regulation of a range of cellular processes, including proliferation, adhesion, motility and survival (for a review see Yeatman or Rucci et al. 4,5 ). It is the best-characterized member of the Src family kinases (SFKs), a family of 9 similar proteins that also includes Blk, Fgr, Fyn, Hck, Lck, Lyn, Yes and Yrk. 4,5 SFK members share a unique domain and 3 other domains termed the kinase domain and Src homology (SH) domains SH2 and SH3. The kinase domain phosphorylates tyrosine residues in substrates that bind to the SH...

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“…Constitutively activated (Y501F) and inactive variants (K269R) of human Hck were generated by polymerase chain reaction (PCR) as described previously (Warmuth et al, 1997) and cloned into the EcoRI site of a pMSCV IRESwt/EGFP vector (gift from R Van Etten) as described (Warmuth et al, 2003). For transient expression of chimeric EpoR-gp130 and Hck, constructs employing the vectors pCDNA6 and pApuro, respectively, were used (Schaeffer et al, 2001).…”

Section: Dna-constructsmentioning

confidence: 99%

“…The generation of retroviral stocks and infection of target cells were performed as described previously (Warmuth et al, 2003). GFP-expressing retrovirus-transduced cells were selected by flow-cytometric cell sorting on a modular flow cytometer (Cytomation Inc., Fort Collins, CO, USA).…”

Section: Retroviral Transductionmentioning

confidence: 99%

Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases

Hausherr¹,

Tavares²,

Schäffer³

et al. 2007

Oncogene

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An acidic domain (AD) of gp130 was previously found to interact with the Src family kinase (SFK) Hck. Here, the influence of myristoylated peptides derived from this AD was assessed in the mouse myeloma cell line, 7TD1. The IL-6-dependent growth of 7TD1 cells was reduced by B75%, if 100 lM of myristoylated 18mer peptide (18AD) was included in the growth medium, but was unaffected by a control peptide with scrambled sequence (18sc). A similar differential inhibition by peptides 18AD and 18sc was observed for the erythropoietin-dependent growth of BaF-EH cells expressing chimeric erythropoietin receptor-gp130 and human Hck and for the human myeloma cell line INA-6. While the peptide 18AD concentration inhibiting 50% was B30 lM in 7TD1 and BaF-EH cells, peptide 18AD did not significantly inhibit growth of IL-6-independent MM1.S myeloma and OKT1 hybridoma cells or of BaF-EH cells supplied with IL-3. Treatment with 100 lM peptide 18AD caused the same degree or 60% of apoptosis induction as IL-6 deprivation in 7TD1 or INA-6 cells, respectively. Co-immunoprecipitation experiments revealed that peptide 18AD interfered with the association of Hck and gp130 in 7TD1 lysates in a concentrationdependent manner. IL-6-treatment of INA-6 cells induced the kinase activities of Fyn, Lyn and Hck, but not Src, and the IL-6-induced SFK activities were inhibited by peptide 18AD. Expression in 7TD1 cells of a kinaseinactive Hck mutant (K269R) elicited a dominantnegative effect on cell number increases providing further evidence that SFKs are required for gp130 signalling in myeloma cells.

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Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate–resistant Bcr-Abl kinases

Cited by 127 publications

References 27 publications

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

Targeting Src signaling in metastatic bone disease

Inhibition of IL-6-dependent growth of myeloma cells by an acidic peptide repressing the gp130-mediated activation of Src family kinases

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