Tumor selective G(2)/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine

Two distinct benzodiazepine binding sites have been identified, (i) a centr al site restricted to brain and (ii) a ubiquitously expressed mitochondrial binding site, the so-called peripheral-type benzodiazepine receptor (PBR). In this paper, we show that a benzazepine referred to as BBL22 (2-amino 9- chloro-7-(2-fluorophenyl)-5H-pyrimidol[5.4-d][2]benzazepine). which is clas sified as a PER ligand based on structure, induces arrest in G(2)/M phase o f the cell cycle in human tumor cell lines of both epithelial and hematopoi etic cellular origin. After G(2)/M arrest, several tumor types, notably pro state and certain breast cancer lines exhibited significant apoptosis. Idea lly, cancer therapies should selectively target tumor cells while sparing n ormal cell counterparts. BBL22 exhibited such selectivity, as it did not af fect the growth and survival of nonmalignant breast and prostate epithelial lines. Moreover. BBL22 demonstrated structural requirements for this selec tive antitumor activity as 11 structurally related PER ligands, including h igh-affinity ligands Ro5-4864 and PK11195, failed to induce tumor cell grow th arrest or apoptosis. The in vivo antitumor activity of BBL22 was examine d in a human xenograft model of androgen-independent prostate cancer where BBL22 significantly reduced the growth of PC3 prostate tumors without elici ting overt toxicity. Identification of BBL22 represents a tumor selective t herapeutic strategy for a variety of human tumors.