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

Abstract

Z-1,1-Dichloro-2,3-diphenylcyclopropane (A(II)) has long been known to be active against models of breast carcinoma. Microtubule perturbation and interaction at type II estrogen binding sites mediate its actions. Since these targets are potentially useful for treatment of prostate 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 cytometry, and electrophoresis. At 100 microM, A(II) reduced survival of both lines by 50% in 12-24 hr, whereas 10 microM A(II) caused a prolonged block of proliferation in both lines, and parallel and complete block of PSA in LNCaP cells. At 10 microM, A(II) caused no major changes in chromatin, morphology or cell cycle distributions, whereas 100 microM drug caused rapid, large-scale cell detachment, nuclear 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 cell growth, caused little hypodiploidy, but potently and dose-dependently caused G(2)/M accumulation. These and previous data suggest that the Z-1, 1-dichloro-2,3-diarylcyclo-propanes may be useful in the treatment of human prostate disease.