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

Abstract

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 [1alpha,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)betagamma-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 RARbeta. Stable expression of RARbeta into the RARbeta-negative PC-3 cells resulted in increased sensitivity to SR11262 and LH proportional to the amount of RARbeta expressed. This study indicates that RARbeta 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.

Synergistic inhibition of prostate cancer cell lines by a 19- nor hexafluoride vitamin D3 analogue and anti-activator protein 1 retinoid

“…This is intriguing because PC-3 cells are more transformed than LNCaP cells (Carrol et al, 1993;Gaddipati et al, 1994;Issacs et al, 1994;Ewing et al, 1995;Tamimi et al, 1996) and, in particular, do not express RAR-β, whereas LNCaP cells do. This is possibly reflected by the reduced sensitivity of PC-3 cells to LH and various retinoids as found in the present study, and more comprehensively in the previous one (Campbell et al, 1998b). Strikingly, in PC-3 cells, antiproliferative potency appears to be retained by anti-AP-1 retinoids in combination with LH.…”

“…Previously, we have shown synergistic inhibition of prostate cancer cell proliferation by LH and certain novel and naturally occurring retinoids, and that a loss of synergistic inhibition correlated with loss of expression of RAR-β (Campbell et al, 1998b). However, this previous study was not able to assess to what extent the anti-AP-1 effects of retinoids contributed to the inhibitory behaviour.…”

“…Unfortunately, this analogue also causes hypercalcaemia at high doses (Pakkala et al, 1995). In a preliminary study to enhance the action of this compound, we investigated combinations of LH with various naturally occurring and receptor-selective retinoids that transactivate through either RARE or RXRE (Campbell et al, 1998b) and demonstrated that the capacity for synergistic effects was reduced with increased cellular transformation. We have now investigated a synthetic retinoid that has predominately anti-AP-1 effects, as few anti-cancer studies have focused on the contribution of AP-1 repression to retinoid-mediated inhibitory effects.…”

Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice

“…The lack of ATRAinduced CYP26 in both PC3 and DU145 cells may be due to the loss of RARs in these cell lines. Several investigators have reported that the loss of RAR signaling in many epithelial tumours is driven by loss of expression of RARs (Campbell et al, 1998;Zhang, 2002).…”

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

“…The interactions of two compounds were assessed by measuring the mean effect of either compound acting alone (F SE; refs. 20,21,33). The combination of the mean effect for each compound acting alone was the predicted combined inhibition.…”