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

• Published in: The Prostate 2000-12, Vol.45 (4), p.277-288
• Main Authors: Balachandran, Raghavan, Grant, Stephen G., Welsh, Manda J., Day, Billy W.
• Format: Article
• Language: English
• Subjects: Androgens - physiology; antimitotic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; cell cycle; Cell Cycle - drug effects; Cell Division - drug effects; DNA Fragmentation; Dose-Response Relationship, Drug; Estrogen Receptor Modulators - pharmacology; flow cytometry; Genital system. Reproduction; Growth Inhibitors - pharmacology; Humans; Male; Medical sciences; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - immunology; Neoplasms, Hormone-Dependent - pathology; Pharmacology. Drug treatments; prostate-specific antigen; Prostate-Specific Antigen - antagonists & inhibitors; Prostate-Specific Antigen - biosynthesis; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Tumor Cells, Cultured - drug effects
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/1097-0045(20001201)45:4<277::AID-PROS1>3.0.CO;2-W

BACKGROUND Z‐1,1‐Dichloro‐2,3‐diphenylcyclopropane (AII) 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. METHODS 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. RESULTS At 100 μM, AII reduced survival of both lines by 50% in 12–24 hr, whereas 10 μM AII caused a prolonged block of proliferation in both lines, and parallel and complete block of PSA in LNCaP cells. At 10 μM, AII caused no major changes in chromatin, morphology or cell cycle distributions, whereas 100 μM 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 AII, 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 G2/M accumulation. CONCLUSIONS 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. Prostate 45:277–288, 2000. © 2000 Wiley‐Liss, Inc.