EFFECTS OF RETINOID-X RECEPTOR-SELECTIVE LIGANDS ON PROLIFERATION OF PROSTATE-CANCER CELLS

BACKGROUND. Management of prostate cancer that either is detectable by prostate specific antigen (PSA) measurements after curative intent or has spread outside of its capsule is a serious problem. innovative, n ontoxic approaches to the disease are required. One approach might be therapy with retinoids. Retinoid activities are mediated by two distin ct families of transcription factors: the retinoic acid receptors (RAR s) and retinoid X receptors (RXRs), which can induce transcriptional a ctivation through specific DNA sites or by inhibiting the transcriptio n factor AP-1 that usually mediates cellular proliferative signals. Th e RARs require heterodimerization with RXRs. RXRs can form either hete rodimers or homodimers; and the latter can bind to DNA response elemen ts that are distinct from those bound by the RAR/RXR heterodimers. MET HODS. A series of novel synthetic retinoids that selectively interact with RXR/RXR homodimers or RAR/RXR heterodimers, or that selectively i nhibit AP-1 activity without activating transcription were evaluated f or their ability to inhibit clonal growth of three human prostate canc er cell lines (PC-3, DU-145, and LNCaP). RESULTS. Several notable find ings were: 1) RXR-selective retinoids, such as SR11246, were able to i nhibit the clonal growth of prostate cancer cells. In contrast, SR1124 6 had little effect on clonal growth of myeloid leukemic cells. 2) RAR -selective retinoids also inhibited clonal growth of prostate cancer c ells. 3) The retinoid (SR11238) with potent anti-AP-1 activity had no effect on the clonal growth of prostate cancer cells. CONCLUSIONS. Thi s study shows that both RXR- and RAR-selective retinoids are worthy of further study and may be candidates for future clinical trials in pro state cancer. (C) 1997 Wiley-Liss, Inc.