Tumor selective G2/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 central 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 classified as a PBR ligand based on structure, induces arrest in G(2)/M phase of the cell cycle in human tumor cell lines of both epithelial and hematopoietic cellular origin. After G(2)/M arrest, several tumor types, notably prostate and certain breast cancer lines exhibited significant apoptosis. Ideally, cancer therapies should selectively target tumor cells while sparing normal cell counterparts. BBL22 exhibited such selectivity, as it did not affect the growth and survival of nonmalignant breast and prostate epithelial lines. Moreover, BBL22 demonstrated structural requirements for this selective antitumor activity as 11 structurally related PBR ligands, including high-affinity ligands Ro5-4864 and PK11195, failed to induce tumor cell growth arrest or apoptosis. The in vivo antitumor activity of BBL22 was examined in a human xenograft model of androgen-independent prostate cancer where BBL22 significantly reduced the growth of PC3 prostate tumors without eliciting overt toxicity. Identification of BBL22 represents a tumor selective therapeutic strategy for a variety of human tumors.
Xia
W
W
Division of Hematology/Oncology, Department of Medicine, University of Miami School of Medicine, Miami, FL 33136, USA.
Spector
S
S
Hardy
L
L
Zhao
S
S
Saluk
A
A
Alemane
L
L
Spector
N L
NL
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C411292:BBL22 benzazepine; D001552:Benzazepines