bcl-2 inhibits mitochondrial metabolism and lonidamine-induced apoptosis in adriamycin-resistant MCF7 cells

Lonidamine (LND), a selective inhibitor of the energy metabolism of tumor c ells, induces apoptosis, independently of the p53 gene, in the adriamycin(A DR)-resistant MCF7 breast cancer cell line (MCF7 ADR). On the contrary, LND fails to activate the apoptotic program in the parental MCF7-sensitive cel l line (MCF7 WT). The extent of bcl-2 expression might account for the diff erent effect of LND on these cell lines. In fact, the MCF7 ADR line shows a low level of bcl-2 protein, whereas MCF7 WT expresses a high level of bcl- 2, We therefore investigated the relationship between the amount of bcl-2 a nd the ability of LND to induce apoptosis, using 4 clones over-expressing b cl-2. The effect of bcl-2 on the energy metabolism was also evaluated. We d emonstrated that over-expression of bcl-2 inhibited LND induced apoptosis, while reducing (CO2)-C-14 production, oxygen uptake and ATP content, wherea s aerobic lactate production was essentially unaffected. In addition, LND d ecreased the oxidative metabolism of the MCF7 ADR cells to a greater extent than it did in the bcl-2 transfectants, (C) 1999 Wiley-Liss, Inc.