Coadministration of UCN-01 with MEK1/2 Inhibitors Potently Induces Apoptosis in

Yu, Chunrong; Dai, Yun; Dent, Paul; Grant, Steven

doi:10.4161/cbt.319

Cited by 23 publications

(16 citation statements)

References 38 publications

(42 reference statements)

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“…5B). In contrast, UCN-01 did not decrease but instead increased the activity of a distinct signaling route that leads to activation of extracellular signal-regulated kinases, as previously reported (22,26), thus supporting the specificity of this effect on the Akt pathway.…”

Section: Resultssupporting

confidence: 51%

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Amornphimoltham

Sriuranpong

Patel

et al. 2004

Clinical Cancer Research

165

143

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Squamous carcinomas of the head and neck (HNSCC) represent the sixth most common cancer among men worldwide and a major cause of morbidity and mortality due to its relatively poor prognosis. As part of ongoing studies addressing the molecular events underlying tumor progression in HNSCC, we have explored the nature of the proliferative pathways in which dysregulation may promote aberrant cell growth in this tumor type. The serine/threonine protein kinase Akt is a downstream target of phosphatidylinositol 3-kinase and a key regulator of normal and cancerous growth and cell fate decisions. Therefore, in this study, we have examined the status of activation of Akt in different stages of squamous cell carcinoma development in mice and in clinical samples from HNSCC patients. By immunohistochemical analysis, using a recently developed phosphorylation state-specific antibody, we demonstrated that Akt activation correlates closely with the progression of mouse skin squamous cell carcinoma. We also observed that activation of Akt is a frequent event in human HNSCC because active Akt can be detected in these tumors with a pattern of expression and localization correlating with the progression of the lesions. In line with these observations, Akt was constitutively activated in a large fraction of HNSCCderived cell lines. We also provide evidence that the Akt signaling pathway may represent a biologically relevant target for a novel antineoplastic agent, UCN-01, which recently has been shown to be active in cellular and xenograft models for HNSCC at concentrations safely achievable in clinically relevant situations.

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Section: Resultssupporting

confidence: 51%

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Amornphimoltham

Sriuranpong

Patel

et al. 2004

Clinical Cancer Research

165

143

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“…As such, efforts towards simultaneous inhibition of ERK or other signalling pathways may be a more effective approach to treating drug-resistant cancer cells. For example, simultaneous inhibition of the PKC, Chk1, and the ERK pathway with UCN-01 and MEK1/2 inhibitors has been shown to be effective in killing leukaemia cells that harbour the BCR-Abl fusion protein and are resistant to the anticancer drug ST1571, also known as Gleevec (Yu et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Activation of extracellular signal‐regulated kinase (ERK) in G₂ phase delays mitotic entry through p21^CIP1

2006

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Extracellular signal-regulated kinase activity is essential for mediating cell cycle progression from G 1 phase to S phase (DNA synthesis). In contrast, the role of extracellular signal-regulated kinase during G 2 phase and mitosis (M phase) is largely undefined. Previous studies have suggested that inhibition of basal extracellular signal-regulated kinase activity delays G 2 -and M-phase progression. In the current investigation, we have examined the consequence of activating the extracellular signalregulated kinase pathway during G 2 phase on subsequent progression through mitosis. Using synchronized HeLa cells, we show that activation of the extracellular signal-regulated kinase pathway with phorbol 12-myristate 13-acetate or epidermal growth factor during G 2 phase causes a rapid cell cycle arrest in G 2 as measured by flow cytometry, mitotic indices and cyclin B1 expression. This G 2 -phase arrest was reversed by pretreatment with bisindolylmaleimide or U0126, which are selective inhibitors of protein kinase C proteins or the extracellular signal-regulated kinase activators, MEK1/2, respectively. The extracellular signal-regulated kinase-mediated delay in M-phase entry appeared to involve de novo synthesis of the cyclin-dependent kinase inhibitor, p21 CIP1 , during G 2 through a p53-independent mechanism. To establish a function for the increased expression of p21 CIP1 and delayed cell cycle progression, we show that extracellular signal-regulated kinase activation in G 2 -phase cells results in an increased number of cells containing chromosome aberrations characteristic of genomic instability. The presence of chromosome aberrations following extracellular signal-regulated kinase activation during G 2 -phase was further augmented in cells lacking p21 CIP1 . These findings suggest that p21 CIP1 mediated inhibition of cell cycle progression during G 2 /M phase protects against inappropriate activation of signalling pathways, which may cause excessive chromosome damage and be detrimental to cell survival.

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“…In addition, a more potent MEK1/2 inhibitor with superior pharmacokinetic characteristics (PD0325901) is currently undergoing clinical evaluation (40). In this context, it is notable that several laboratories, including our own, have shown that MEK1/2 inhibitors such as PD184352 potentiate the lethality of various other targeted agents, including the small-molecule Bcl-2 antagonist HA14-1 (41), the Chk1 inhibitor UCN-01 (30), and, in Bcr/abl + leukemia cells, Bcr/abl kinase inhibitors such as imatinib mesylate (26) as well as histone deacetylase inhibitors (42). Because Hsp90 antagonists can themselves down-regulate the Raf/MEK1/2/ERK1/2 pathway (43), it is not intuitively obvious why a MEK1/2 inhibitor should lower the apoptotic threshold for an agent such as DMAG.…”

Section: Discussionmentioning

confidence: 99%

“…30), as well as the preclinical evidence of activity of Hsp90 antagonists in Bcr/abl + hematopoietic malignancies (27,28,31), the possibility arose that these agents might cooperate to trigger apoptosis in Bcr/abl + leukemia cells. The goal of the present studies was to determine whether and by what mechanism the clinically relevant MEK1/2 inhibitor PD184352 might enhance the activity of DMAG against Bcr/abl + leukemia cells.…”

mentioning

confidence: 99%

Synergistic Interactions between DMAG and Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitors in Bcr/abl+ Leukemia Cells Sensitive and Resistant to Imatinib Mesylate

Nguyen

Rahmani

Gao

et al. 2006

Clinical Cancer Research

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Purpose:To characterize interactions between the heat shock protein 90 antagonist 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and the mitogen-activated protein kinase/extracellular signal^regulated kinase (ERK) kinase 1/2 inhibitor PD184352 in Bcr/abl + leukemia cells sensitive and resistant to imatinib mesylate. Experimental Design: K562 and LAMA 84 cells were exposed to varying concentrations of DMAG and PD184352 for 48 hours; after which, mitochondrial integrity, caspase activation, and apoptosis were monitored. Parallel studies were done in imatinib mesylate^resistant cells, including BaF3 cells transfected with plasmids encoding clinically relevant Bcr/abl mutations conferring imatinib mesylate resistance (e.g., E255K, M351T, and T315I) and primary CD34 + bone marrow cells from patients refractory to imatinib mesylate. Results: Cotreatment of Bcr/abl + cells with minimally toxic concentrations of DMAG and PD184352 resulted in synergistic induction of mitochondrial injury (cytochrome c release and Bax conformational change), events associated with the pronounced and sustained inactivation of ERK1/2 accompanied by down-regulation of Bcl-x L . Conversely, cells ectopically expressing Bcl-x L displayed significant protection against PD184352/DMAG^mediated lethality. This regimen effectively induced apoptosis in K562 cells overexpressing Bcr/abl, in BaF3 cells expressing various clinically relevant Bcr/abl mutations, and in primary CD34 + cells from patients resistant to imatinib mesylate, but was relatively sparing of normal CD34 + bone marrow cells. Conclusions: A regimen combining the heat shock protein 90 antagonist DMAG and the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor potently induces apoptosis in Bcr/abl + cells, including those resistant to imatinib mesylate through various mechanisms including Bcr/abl kinase mutations, through a process that may involve sustained ERK1/2 inactivation and Bcl-x L down-regulation.This strategy warrants further attention in Bcr/abl + hematopoietic malignancies, particularly those resistant to Bcr/abl kinase inhibitors.

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Coadministration of UCN-01 with MEK1/2 Inhibitors Potently Induces Apoptosis in

Cited by 23 publications

References 38 publications

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Activation of extracellular signal‐regulated kinase (ERK) in G₂ phase delays mitotic entry through p21^CIP1

Synergistic Interactions between DMAG and Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitors in Bcr/abl+ Leukemia Cells Sensitive and Resistant to Imatinib Mesylate

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Coadministration of UCN-01 with MEK1/2 Inhibitors Potently Induces Apoptosis in

Cited by 23 publications

References 38 publications

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma

Activation of extracellular signal‐regulated kinase (ERK) in G2 phase delays mitotic entry through p21CIP1

Synergistic Interactions between DMAG and Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitors in Bcr/abl+ Leukemia Cells Sensitive and Resistant to Imatinib Mesylate

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Activation of extracellular signal‐regulated kinase (ERK) in G₂ phase delays mitotic entry through p21^CIP1