1,25-Dihydroxyvitamin D3 and 9-cis-Retinoic Acid Act Synergistically to Inhibit the Growth of LNCaP Prostate Cells and Cause Accumulation of Cells in G1*

Abstract

Recent studies have suggested that the active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, can inhibit the growth and/or induce the differentiation of a variety of cell types and that these characteristics might be useful in the treatment of some cancers. Retinoids also promote the differentiation and inhibit the growth of some cells. That the vitamin D receptor acts as a heterodimer with the retinoid X receptor (RXR) suggests that there may be functional interactions between 1,25-dihydroxyvitamin D3 and retinoids. In this study, we show that the combination of 1,25-dihydroxyvitamin D3 and 9-cis retinoic acid synergistically inhibits the growth of LNCaP prostate cancer cells. That this effect is mediated by RXR rather than retinoic acid receptors was shown using RXR- and retinoic acid receptor-specific ligands. The vitamin D3 analog, EB1089, inhibited growth more effectively than 1,25-dihydroxyvitamin D3 and also acted synergistically with 9-cis-retinoic acid. These treatments caused cells to accumulate in the G1 phase of the cell cycle, suggesting that 1,25-dihydroxyvitamin D3 can regulate one or more factors critical for the G1/S transition.

Synergistic Effect of Vitamin D Derivatives and Retinoids on C2C12 Skeletal Muscle Cells

“…The data found associating vitamin D derivatives and retinoids are in accordance with the results obtained by many authors, who described a synergistic effect exerted by 1,25(OH) 2 D 3 or its analogues and retinoids on different cell lines (35-37). Blutt et al (38) reported the synergistic inhibition in the growth of LNCaP prostate cancer cells exerted by the combination of 1,25(OH) 2 D 3 or EB 1089 and 9-cis retinoic acid, and Zugmayer et al (39) showed that EB 1089, if added alone to human pancreatic adenocarcinoma cells, did not significantly inhibit growth, while, in combination with all-trans retinoic acid caused a growth-inhibitory effect of 90%. We also demonstrated the synergistic effect exerted by the combination of 1,25(OH) 2 D 3 or its analogues (KH 1060 and EB 1089) and 9-cis retinoic acid on SH-SY5Y human neuroblastoma cell proliferation, whereas the combination with all-trans retinoic acid led to a quite different behaviour (32).…”

Distinct effects of ceramide‐generating pathways in prostate adenocarcinoma cells

“…Our present data, however, strongly support a direct action of IL-1b on the control of LNCaP cell proliferation through activation of the sphingomyelin cascade. 1,25 (OH 2 )-D 3 , which triggers sphingomyelin hydrolysis in di erent cellular systems (Okazaki et al, 1989(Okazaki et al, , 1990, exerts potent antiproliferative and di erentiating activity in LNCaP cells grown in the presence of serum (Skowronski et al, 1993), determining cell cycle arrest in G 1 (Blutt et al, 1997).…”

Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells

“…These VDR/RXR heterodimers function as transcription factors in regulating vitamin D-mediated gene expression (Liao et al, 1990;Kliewer et al, 1992;MacDonald et al, 1993). Several reports have shown that 9-cis-RA and 1,25-VD act synergistically to inhibit the growth of prostate cancer cells via the VDR/RXR heterodimer (Blutt et al, 1997;Zhao et al, 1999).…”

“…Even though these cells express similar levels of functional VDRs, they respond to 1,25-VD-mediated inhibitory effects differently. For example, LNCaP, an androgen-dependent prostate cancer cell line, is significantly inhibited by 1,25-VD; however, the PC-3, DU 145, and ALVA-31 cell lines are less sensitive to the antiproliferative action mediated by 1,25-VD (Miller et al, 1992;Schwartz et al, 1994;Miller et al, 1995;Blutt et al, 1997). These results suggest that VDR expression is not solely responsible for the growth suppression induced by 1,25-VD (Skowronski et al, 1993;Zhuang et al, 1997;Zhuang and Burnstein, 1998).…”