Activation of the c-Jun N-terminal Kinase (JNK) Signaling Pathway Is Essential during PBOX-6-induced Apoptosis in Chronic Myelogenous Leukemia (CML) Cells

Gee, Margaret M. Mc; Campiani, Giuseppe; Ramunno, Anna; Nacci, Vito; Lawler, Mark; Williams, David C.; Zisterer, Daniela M.

doi:10.1074/jbc.m112058200

Cited by 37 publications

(47 citation statements)

References 39 publications

(53 reference statements)

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“…Cells were maintained at 37°C in a humidified incubator with 95% air and 5% CO 2 . The apoptosis assay was performed as described previously (Mc Gee et al, 2002a). Briefly, cells were seeded at 3 ϫ 10 5 cells/ml and after the relevant treatment, an aliquot of cells (150 l) was cytocentrifuged onto a glass slide and stained using the RapiDiff kit as described by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

“…We have shown that PBOX-6 induces apoptosis in K562 cells in a mechanism that bypasses the apoptotic suppressor Bcr-Abl (Mc Gee et al, 2001). We have shown that JNK activation is essential during PBOX-6-induced apoptosis, whereas the activation of caspases is dispensable (Mc Gee et al, 2002a). In this study, we show that PBOX-6 targets antiapoptotic Bcl-2 proteins, resulting in their phosphorylation and inactivation leading to the induction of apoptosis in resistant tumor cells, whereas it has no cytotoxic effect on normal peripheral blood mononuclear cells (PBMCs).…”

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confidence: 91%

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Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL

Greene¹,

Ledwidge²,

Campiani³

et al. 2004

J Pharmacol Exp Ther

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 91%

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL

Greene¹,

Ledwidge²,

Campiani³

et al. 2004

J Pharmacol Exp Ther

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“…Although it is not clear how JNK1 is functionally and mechanistically linked to apoptosis, JNK activity appears to be involved in dual roles in signaling pathways for cell survival and apoptosis in different cell types induced by different stimuli. Some reports have concluded that JNK activity is required for cell survival of various cell types (29,30), while other studies have suggest that JNK activity is required for apoptosis of different cell types (25,31). Such discrepancies in the published literature have been reasoned to be due, at least in part, to specific cell type differences (32).…”

Section: Prolonged Jnk1 Activations During Apoptosis Are Regulatedmentioning

confidence: 99%

The c-Jun N-terminal Kinase 1 Activity Is Differentially Regulated by Specific Mechanisms during Apoptosis

Ham

Choi

Chun

et al. 2003

Journal of Biological Chemistry

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We show here that JNK1 activity is rapidly up-regulated and prolonged by specific mechanisms during apoptosis induced by paclitaxel-or ginsenoside-Rh2 in SK-HEP-1 cells. The early phase of JNK1 activation is prevented in cells expressing the dominant negative SEK1 mutant, although this JNK1 perturbation does not prevent apoptotic cell death. The later phase of JNK1 activation, which is temporally coincided with caspasedependent cleavage of JNK1-associated p21 WAF1/CIP1 , is efficiently prevented by expressing p21D112N, an uncleavable mutant of p21 WAF1/CIP1 and this perturbation of JNK1 activation results in prevention of apoptosis. The later JNK1 activation and apoptotic progression are also prevented by co-treatments of cells with rottlerin, a PKC-␦ inhibitor or z-VAD-fmk, a pan caspase inhibitor. We also provide evidence that apoptotic cell death is significantly promoted in cells expressing JNK1, while this apoptotic cell death is effectively suppressed in cells expressing the dominant negative JNK1 mutant (DN-JNK1) or JBD, a JNK inhibitor protein. Thus, the later phase of JNK1 activation, which is linked to a caspase-dependent mechanism that requires PKC-␦ activity, is associated with the induction of apoptosis, while the early JNK1 activation that is associated with a SEK1-mediated mechanism is not directly involved in apoptotic progression.

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“…Our research group have established that some members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds are capable of inducing apoptosis in cancerous cell lines derived from both haematological malignancies [promyelocytic leukaemia HL60 cells, Jurkat T-lymphoma cells, Hut-78 lymphoma cells, T cell leukaemia CEM cells and chronic myeloid leukaemia (CML) K562 cells] and solid tumours (breast carcinoma MCF-7 cells and ovarian A2780 cells) (5)(6)(7)(8)(9)(10). These results are supported by studies revealing impaired growth of tumours in a mouse 4T1 breast carcinoma tumour model (11), and a CML mouse model (12) and apoptosis in ex vivo CML and chronic lymphocytic leukaemia (CLL) patient samples (12,13).…”

Section: Introductionmentioning

confidence: 99%

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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Abstract. Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce antiproliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G 2 /M arrest. G 2 /M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of antiapoptotic proteins Bcl-2 and Bcl-x L and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G 2 /M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-x L . Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOXinduced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer. IntroductionProstate cancer is the leading cause of cancer and the second leading cause of cancer-related deaths among men in Europe and the USA (1). Early diagnosis following widespread PSA screening has resulted in most patients presenting with localized tumours. These patients generally exhibit good survival rates following radiotherapy or surgery. However, a number of patients still progress to or are diagnosed with locally advanced or metastatic tumours. While androgendeprivation therapy can slow the development of advanced metastatic prostate cancer, most tumours will still progress within a few years to an androgen-independent state (2). At this stage, treatment options become limited. The current treatment of choice for patients with advanced hormonerefractory prostate cancer is docetaxel-based chemotherapy. While these treatments significantly improve the overall survival of patients (3,4), the prognosis still remains poor for patients presenting with advanced stage prostate cancer. Therefore, the development of improved treatments and combinations are required.Our research group have established that some members of the pyrrolo-1,5-benzoxazepine (PBOX) famil...

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Activation of the c-Jun N-terminal Kinase (JNK) Signaling Pathway Is Essential during PBOX-6-induced Apoptosis in Chronic Myelogenous Leukemia (CML) Cells

Cited by 37 publications

References 39 publications

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL

The c-Jun N-terminal Kinase 1 Activity Is Differentially Regulated by Specific Mechanisms during Apoptosis

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

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Activation of the c-Jun N-terminal Kinase (JNK) Signaling Pathway Is Essential during PBOX-6-induced Apoptosis in Chronic Myelogenous Leukemia (CML) Cells

Cited by 37 publications

References 39 publications

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH2-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-XL

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH2-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-XL

The c-Jun N-terminal Kinase 1 Activity Is Differentially Regulated by Specific Mechanisms during Apoptosis

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

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Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL

Selective Induction of Apoptosis by the Pyrrolo-1,5-benzoxazepine 7-[{Dimethylcarbamoyl}oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) in Leukemia Cells Occurs via the c-Jun NH₂-Terminal Kinase-Dependent Phosphorylation and Inactivation of Bcl-2 and Bcl-_XL