TY - JOUR
T1 - Bcl-2 phosphorylation in a human breast carcinoma xenograft
T2 - A common event in response to effective DNA-damaging drugs
AU - Pratesi, Graziella
AU - Polizzi, Donatella
AU - Perego, Paola
AU - Dal Bo, Laura
AU - Zunino, Franco
PY - 2000/7
Y1 - 2000/7
N2 - A variety of cytotoxic agents effective as antitumor drugs are known to kill tumor cells through induction of apoptosis as the most relevant modality of cell death. A specific role for the protein Bcl-2 in the cell death pathway induced by antimicrotubule agents has been proposed, because Bcl-2 phosphorylation occurs in response to microtubule damage. In this study, we compared efficacy, apoptosis, and Bcl-2 phosphorylation in the Bcl-2-overexpressing MX-1 human breast carcinoma xenograft after treatment with cytotoxic agents characterized by different mechanisms of action. We demonstrated that, in addition to antimicrotubule agents, effective DNA-damaging agents were also able to induce Bcl-2 phosphorylation irrespective of the type of genotoxic lesion. A comparison of effects of drugs belonging to the same class but endowed with a different antitumor activity (i.e. cisplatin versus a novel multinuclear platinum complex and doxorubicin versus a disaccharide analogue) showed a correlation between drug efficacy, apoptotic response, and Bcl-2 phosphorylation. In conclusion, overexpression of Bcl-2 did not counteract the apoptotic effects of a number of cytotoxic agents and could not be regarded as a mechanism of cellular resistance. Since Bcl-2 phosphorylation is a common event in response to different types of cytotoxic damage and is not only related to microtubule dysfunction, we suggest that many cell death pathways converge on Bcl-2 and protein phosphorylation is a step of the signaling cascade activated by diverse stimuli and likely related to the onset of drug-induced apoptosis. Copyright (C) 2000 Elsevier Science Inc.
AB - A variety of cytotoxic agents effective as antitumor drugs are known to kill tumor cells through induction of apoptosis as the most relevant modality of cell death. A specific role for the protein Bcl-2 in the cell death pathway induced by antimicrotubule agents has been proposed, because Bcl-2 phosphorylation occurs in response to microtubule damage. In this study, we compared efficacy, apoptosis, and Bcl-2 phosphorylation in the Bcl-2-overexpressing MX-1 human breast carcinoma xenograft after treatment with cytotoxic agents characterized by different mechanisms of action. We demonstrated that, in addition to antimicrotubule agents, effective DNA-damaging agents were also able to induce Bcl-2 phosphorylation irrespective of the type of genotoxic lesion. A comparison of effects of drugs belonging to the same class but endowed with a different antitumor activity (i.e. cisplatin versus a novel multinuclear platinum complex and doxorubicin versus a disaccharide analogue) showed a correlation between drug efficacy, apoptotic response, and Bcl-2 phosphorylation. In conclusion, overexpression of Bcl-2 did not counteract the apoptotic effects of a number of cytotoxic agents and could not be regarded as a mechanism of cellular resistance. Since Bcl-2 phosphorylation is a common event in response to different types of cytotoxic damage and is not only related to microtubule dysfunction, we suggest that many cell death pathways converge on Bcl-2 and protein phosphorylation is a step of the signaling cascade activated by diverse stimuli and likely related to the onset of drug-induced apoptosis. Copyright (C) 2000 Elsevier Science Inc.
KW - Anthracycline
KW - Apoptosis
KW - Bcl-2
KW - Cisplatin
KW - Taxane
KW - Tumor xenografts
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U2 - 10.1016/S0006-2952(00)00300-2
DO - 10.1016/S0006-2952(00)00300-2
M3 - Article
C2 - 10807947
AN - SCOPUS:0034055659
VL - 60
SP - 77
EP - 82
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 1
ER -