The antiproliferative effect of 8-chloro-adenosine, an active metabolite of 8-chloro-cyclic adenosine monophosphate, and disturbances in nucleic acid synthesis and cell cycle kinetics

Langeveld, Cornelis H.; Jongenelen, Cornelis A.M.; Theeuwes, Johannes Wilhelmus M.; Baak, Johannes P.A.; Heimans, Johannes J.; Stoof, Johannes C.; Peters, Godefridus J.

doi:10.1016/s0006-2952(96)00593-x

Cited by 42 publications

(36 citation statements)

References 21 publications

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“…On the contrary, several lines of evidence indicate that the regulation of PKA-R subunits by 8-Cl-cAMP is not the major cause of growth inhibition (18)(19)(20)36). 8-Cl-cAMP could not induce growth inhibition in the presence of IBMX (a phosphodiesterase inhibitor) and A134974 (an adenosine kinase inhibitor), which lead to the blockage of 8-Cl-cAMP metabolic pathway (20).…”

Section: Discussionmentioning

confidence: 99%

“…8-Cl-cAMP can be converted to 8-Cl-adenosine by the actions of phosphodiesterase and nucleotide phosphatase, and 8-Cl-adenosine is further metabolized by adenosine kinase into 8-Cl-AMP or 8-Cl-ATP. In many experimental systems, 8-Cl-cAMP must be metabolized to induce growth inhibition; nevertheless, it is still debatable (18)(19)(20)36). It cannot be overlooked that down-regulation of PKA-RI subunit by 8-Cl-cAMP is a critical aspect during the induction of growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

2005

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8-Chloro-cyclic AMP (8-Cl-cAMP), which is known to induce growth inhibition, apoptosis, and differentiation in various cancer cell lines, has been studied as a putative anticancer drug. However, the mechanism of anticancer activities of 8-ClcAMP has not been fully understood. Previously, we reported that the 8-Cl-cAMP-induced growth inhibition is mediated by protein kinase C (PKC) activation. In this study, we found that p38 mitogen-activated protein kinase (MAPK) also plays important roles during the 8-Cl-cAMP-induced growth inhibition and apoptosis. SB203580 (a p38-specific inhibitor) recovered the 8-Cl-cAMP-induced growth inhibition and apoptosis, whereas other MAPK inhibitors, such as PD98059 (an extracellular signal-regulated kinase-specific inhibitor) and SP600125 (a c-Jun NH 2 -terminal kinase-specific inhibitor), had no effect. The phosphorylation (activation) of p38 MAPK was increased in a time-dependent manner after 8-ClcAMP treatment. Furthermore, SB203580 was able to block PKC activation induced by 8-Cl-cAMP. However, PKC inhibitor (GF109203x) could not attenuate p38 activation, indicating that p38 MAPK activation is upstream of PKC activation during the 8-Cl-cAMP-induced growth inhibition. 8-Chloroadenosine, a metabolite of 8-Cl-cAMP, also activated p38 MAPK and this activation was blocked by adenosine kinase inhibitor. These results suggest that 8-Cl-cAMP exerts its anticancer activity through p38 MAPK activation and the metabolite(s) of 8-Cl-cAMP mediates this process. (Cancer Res 2005; 65(11): 4896-901)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

2005

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“…In fact, our data suggest that, even if the 8-Cl-cAMP effect on ERKs activation is mediated through RIα down-regulation, this effect does not occur by depressing the function or the cellular content of EGF-R in our epidermoid tumour cell system. Furthermore, it has been hypothesized that 8-Cl-adenosine, the metabolite derived from 8-Cl-cAMP phosphodiesterase-mediated degradation, can be responsible for the growth-inhibitory effects of this agent (Lange-Carter et al, 1993;Langeveld et al, 1997). However, other investigations have demonstrated that the antitumour activity of 8-Cl-cAMP is not dependent on its metabolite (Tagliaferri et al, 1988;Rohlff et al, 1993;Cho-Chung et al, 1995;Noguchi et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Results are representative of three independent experiments in triplicate determinations; standard errors never exceeded 10%; *P<0.005 as compared to controls ERK-1 activity in response to both EGF and PMA. Moreover, it was previously shown that 8-Cl-cAMP can be hydrolysed to 8-Cladenosine by the serum-phosphodiesterases and 5′-nucleotidase and has been hypothesized that the latter molecule can be indeed responsible for the effects of 8-Cl-cAMP (Lange-Carter et al, 1993;Langeveld et al, 1997). However, in our experimental conditions, the inhibition of ERK-1 activity induced by 8-Cl-cAMP was not due to the metabolite because 8-Cl-adenosine, while inducing over 50% cell growth inhibition (data not shown), did not modify EGF-stimulated or PMA-stimulated ERK-1 activity ( Figure 2D).…”

Section: Effect Of 8-cl-camp On Dna Synthesis and Erks Activationmentioning

confidence: 99%

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

et al. 1999

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SummaryThe growth factor-activated mitogenic pathways are often disregulated in tumour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a novel anti-tumour agent that has recently undergone clinical evaluation. We investigated the effects of 8-CI-cAMP on the epidermal growth factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are responsive to the mitogenic stimulus of EGF. We found that the growthpromoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-CI-cAMP. The inhibition of the EGF-induced proliferation by 8-CI-cAMP was paralleled by the blockade of the EGF-stimulated activation of mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activators upstream MAPK in the phosphorylation cascade induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibition of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved.

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“…20 Furthermore, the actions of the analog were DNA independent and RNA directed. 20,23 Finally, incorporation of the analog into RNA results in inhibition of global RNA synthesis with maximal effect on mRNA production. 24 Taken together these characteristics make the halogenated adenosine triphosphate (8-Cl ATP) an ideal drug to target transcription and cellular bioenergy of replicationally quiescent CLL lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP

Balakrishnan

Stellrecht

Genini

et al. 2005

Blood

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The antiproliferative effect of 8-chloro-adenosine, an active metabolite of 8-chloro-cyclic adenosine monophosphate, and disturbances in nucleic acid synthesis and cell cycle kinetics

Cited by 42 publications

References 21 publications

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

8-Chloro-Cyclic AMP–Induced Growth Inhibition and Apoptosis Is Mediated by p38 Mitogen-Activated Protein Kinase Activation in HL60 Cells

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP

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