Z-1,1-dichloro-2,3-diphenylcyclopropanes block human prostate carcinoma cell proliferation, inhibit prostate-specific antigen expression, and initiate apoptosis

BACKGROUND. Z-1,1-Dichloro-2,3-diphenylcyclopropane (A(II)) has long been k nown to be active against models of breast carcinoma. Microtubule perturbat ion and interaction at type II estrogen binding sites mediate its actions. METHODS. Since these targets are potentially useful for treatment of prosta te tumors, we studied the drug's effects on androgen-sensitive (LNCaP) and -independent (PC-3) human prostatic carcinoma lines. Effects on cell growth and morphology, prostate-specific antigen (PSA) expression, and cell cycle kinetics were determined by microscopy, antibody-based methods, flow cytom etry, and electrophoresis. RESULTS. At 100 muM, A(II) reduced survival of both lines by 50% in 12-24 h r, whereas 10 muM A(II) caused a prolonged block of proliferation in both l ines, and parallel and complete block of PSA in LNCaP cells. At 10 muM, A(I I) caused no major changes in chromatin, morphology or cell cycle distribut ions, whereas 100 muM drug caused rapid, large-scale cell detachment, nucle ar and internucleosomal DNA fragmentation, and hypodiploidy. These effects were also accompanied by dissolution of cellular microtubule arrays. A more potent tubulin assembly-inhibiting congener of A(II), Z-1,1-dichloro-2-(4- methoxy-phenyl)-3-phenylcyclopropane, slightly more effectively inhibited c ell growth, caused little hypodiploidy, but potently and dose-dependently c aused G(2)/M accumulation. CONCLUSIONS. These and previous data suggest that the Z-1,1-dichloro-2,3-di arylcyclopropanes may be useful in the treatment of human prostate disease. (C) 2000 Wiley-Liss, Inc.