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(4-benzyl-phenoxy)-ethyl-N-pyrrolidine,HCl (PBPE) is a non-antiestrogen derivative of the antitumoral drug tamoxifen. PBPE is a selective and high affinity ligand of the microsomal antiestrogen binding site (AEBS). We report that PBPE is cytotoxic on tumor cell lines of various origins in a concentration-dependent manner. The potency of PBPE is equivalent to that of tamoxifen. The apoptotic nature of the toxicity induced in MCF-7 by PBPE was characterized by: 1) the condensation of the heterochromatin, 2) the binding annexin-V, 3) the appearence of inter-nucleosomal DNA cleavage, 4) a strong diminution of the Bcl2/Bax ratio, 5) the release of cytochrome C in the cytoplasm. The cytoxicity induced by PBPE, involved both the transcription and the translation of genes, is blocked by vitamine E and C but not by caspase inhibitors, suggesting a caspase-independent active cell death. PBPE and tamoxifen induced a nuclearization the mitochondrial AIF factor that can explain the activation of nucleases. Moreover PBPE and tamoxifen stimulate the accumulation of autophagic vacuoles, the appearence of autophagosomes, the expression of the protein Beclin and the proteolysis of the LC3 protein in cells. Altogether these data demonstrate that PBPE, a non antiestrogen derivative of tamoxifen displayed a high cytotoxic potency on tumoral cells. Moreover we show that PBPE and tamoxifen triggered type II apoptosis or autophagy through a common pathway involving the AEBS.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]