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Endocrinology Vol. 139, No. 4 1972-1980
Copyright © 1998 by The Endocrine Society

ARTICLES

Expression of Retinoic Acid Receptor-ß Sensitizes Prostate Cancer Cells to Growth Inhibition Mediated by Combinations of Retinoids and a 19-nor Hexafluoride Vitamin D3 Analog1

Moray J. Campbell, Susan Park, Milan R. Uskokovic, Marcia I. Dawson and H. Phillip Koeffler2

Division of Hematology/Oncology (M.J.C., S.P., H.P.K.), Cedars-Sinai Medical Center/University of California, Los Angeles School of Medicine, Los Angeles, California 90048; Hoffman La Roche (M.R.U.), Nutley, New Jersey 07110; and SRI International (M.I.D.), Menlo Park, California 94025

Address all correspondence and requests for reprints to: Moray J. Campbell, Ph.D., Department of Immunology, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.

Retinoids and analogs of vitamin D3 may achieve greater in vivo applications if the toxic side effects encountered at pharmacologically active doses could be alleviated. These seco-steroid hormones often act in concert, and therefore, we attempted to dissect these interactions by isolating combinations of receptor-selective retinoids and a potent vitamin D3 analog [1{alpha},25(OH)2-16ene-23-yne-26,27,F6-19nor-D3, code name LH] that were potent inhibitors of prostate cancer cell growth at low, physiologically safer doses.

Using a panel of prostate cancer cell lines representing progressively more transformed phenotypes, we found that the LNCaP cell line (least transformed) was either additively or synergistically inhibited in its clonal growth by LH and various naturally occurring and receptor-selective retinoids, the most potent combination being with a retinoic acid receptor (RAR)ß{gamma}-selective retinoid (SR11262). The effect was not found with either PC-3 (intermediate transformation) or DU-145 (most transformed). We also undertook RT-PCR to examine the subtypes of RARs present, and we found that PC-3 and DU-145 did not express RARß. Stable expression of RARß into the RARß-negative PC-3 cells resulted in increased sensitivity to SR11262 and LH proportional to the amount of RARß expressed.

This study indicates that RARß may play an important role in synergistically controlling cell proliferation, and expression is lost with increased prostate cancer cell transformation. Simultaneous administration of a potent vitamin D3 analog and receptor-selective retinoids may have therapeutic potential for the treatment of androgen-dependent and -independent prostate cancer.




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