Bcl-2 phosphorylation in a human breast carcinoma xenograft: A common event in response to effective DNA-damaging drugs

A variety of cytotoxic agents effective as antitumor drugs are known to kil l 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 path way induced by antimicrotubule agents has been proposed, because Bcl-2 phos phorylation occurs in response to microtubule damage. In this study, we com pared efficacy, apoptosis, and Bcl-2 phosphorylation in the Bcl-2-overexpre ssing MX-1 human breast carcinoma xenograft after treatment with cytotoxic agents characterized by different mechanisms of action. We demonstrated tha t, in addition to antimicrotubule agents, effective DNA-damaging agents wer e also able to induce Bcl-2 phosphorylation irrespective of the type of gen otoxic lesion. A comparison of effects of drugs belonging to the same class but endowed with a different antitumor activity (i.e. cisplatin versus a n ovel multinuclear platinum complex and doxorubicin versus a disaccharide an alogue) showed a correlation between drug efficacy, apoptotic response, and Bcl-2 phosphorylation. In conclusion, overexpression of Bcl-2 did not coun teract the apoptotic effects of a number of cytotoxic agents and could not be regarded as a mechanism of cellular resistance. Since Bcl-2 phosphorylat ion is a common event in response to different types of cytotoxic damage an d 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 th e onset of drug-induced apoptosis. BIOCHEM PHARMACOL 60;1:77-82, 2000. (C) 2000 Elsevier Science Inc.