(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

Thomas, Catherine A.; Grant, Stephen G.; Pflug, Beth R.; Getzenberg, Robert H.; Day, Billy W.

doi:10.1016/j.urolonc.2007.02.013

« Previous Next »Urologic Oncology: Seminars and Original Investigations
Volume 26, Issue 4 , Pages 378-385, July 2008

(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

Catherine A. Thomas, Ph.D.
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
Stephen G. Grant, Ph.D.
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Department of Obstetrics, Gynecology, and Reproductive Sciences and the Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA
Beth R. Pflug, Ph.D.
- Department of Urology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Robert H. Getzenberg, Ph.D.
- University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA
- Department of Urology, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15260, USA
Billy W. Day, Ph.D.
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
- University of Pittsburgh Cancer Institute, Pittsburgh, PA 15260, USA
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Corresponding author. Tel.: +1-412-648-9706, fax: +1-412-383-5298.

Received 16 February 2007; accepted 21 February 2007. published online 14 December 2007.

Abstract

(Z)-1-1-Dichloro-2,3-diphenylcyclopropane (A_II) and (Z)-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane [2-(4-methoxyphenyl)-A_II] inhibit tubulin polymerization, PSA production, and the proliferation of human prostate cancer cells. The actions of the agents were studied in three transgenic adenocarcinomas of the mouse prostate (TRAMP) cell lines. Antiproliferative potencies were determined and cells treated with the more potent 2-(4-methoxyphenyl)-A_II were examined for induction of apoptosis. Microarray analyses were conducted to determine the apoptosis-related genes up- and down-regulated by the agent. 2-(4-Methoxyphenyl)-A_II concentration-dependently inhibited growth of all three cell lines. Fifty percent and 100% growth inhibitory and 50% lethal concentrations were determined to be 0.3, 1.5, and 5 μM, respectively. Minimum detectable apoptosis-inducing concentrations by ELISA were 0.10 to 0.14 μM. PARP cleavage and two-color flow cytometry assays verified apoptosis induction. Microarray analyses showed Bok and Siva-pending to be up-regulated and that Birc, Dad1, and Atf5 were down-regulated. 2-(4-methoxyphenyl)-A_II inhibits proliferation and induces apoptosis in the in vivo-adaptable TRAMP cells, suggesting the compound should be further examined in preclinical models.