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

Abstract

In recent studies, we have identified several highly potent all-trans-retinoic acid (ATRA) metabolism blocking agents (RAMBAs). On the basis of previous effects of liarozole (a first-generation RAMBA) on the catabolism of ATRA and on growth of rat Dunning R3227G prostate tumours, we assessed the effects of our novel RAMBAs on human prostate tumour (PCA) cell lines. We examined three different PCA cell lines to determine their capacity to induce P450-mediated oxidation of ATRA. Among the three different cell lines, enhanced catabolism was detected in LNCaP, whereas it was not found in PC-3 and DU-145. This catabolism was strongly inhibited by our RAMBAs, the most potent being VN/14-1, VN/50-1, VN/66-1, and VN/69-1 with IC 50 values of 6.5, 90.0, 62.5, and 90.0 nM, respectively. The RAMBAs inhibited the growth of LNCaP cells with IC 50 values in the mM-range. In LNCaP cell proliferation assays, VN/14-1, VN/50-1, VN/66-1, and VN/69-1 also enhanced by 47-, 60-, 70-, and 65-fold, respectively, the ATRA-mediated antiproliferative activity. We then examined the molecular mechanism underlying the growth inhibitory properties of ATRA alone and in combination with RAMBAs. The mechanism appeared to involve the induction of differentiation, cell-cycle arrest, and induction of apoptosis (TUNEL), involving increase in Bad expression and decrease in Bcl-2 expression. Treatment of LNCaP tumours growing in SCID mice with VN/66-1 and VN/69-1 resulted in modest but statistically significant tumour growth inhibition of 44 and 47%, respectively, while treatment with VN/14-1 was unexpectedly ineffective. These results suggest that some of our novel RAMBAs may be useful agents for the treatment of prostate cancer.

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

“…This result supports the hypothesis that RAMBA VN/14-1 is able to enhance the biological activity of ATRA through the inhibition of ATRA in vivo. We have demonstrated previously this effect in in vitro breast and prostate cancer models (Patel et al, 2004;Huynh et al, 2006).…”

“…Our RAMBAs are also considered to be atypical, because in addition to being potent inhibitors of ATRA metabolism (able to enhance the antiproliferative action of ATRA), they also possess intrinsic potent cancer antiproliferative activities (Njar et al, 2000(Njar et al, , 2006aNjar, 2002;Patel et al, 2004;Huynh et al, 2006;Belosay et al, 2006). We have also found that our RAMBAs appear to have different potencies in different types of human cancer cell lines.…”

“…These promising results with the ER þ ve breast cancer cells prompted the present study, which examined the molecular mechanisms/biological effects underlying their growth inhibitory potencies. It should be stated that some of the procedure used in this study were identical to those utilised previously (Patel et al, 2004;Huynh et al, 2006). Except where otherwise stated, all cells were assessed following 6 days of ATRA/RAMBAs treatments.…”

“…We have also found that our RAMBAs appear to have different potencies in different types of human cancer cell lines. For example, VN/14-1 is a weak inhibitor of several prostate cancer cells but the compound has been identified as our most potent RAMBA in several breast cancer cell lines (Patel et al, 2004;Belosay et al, 2006;Huynh et al, 2006). Here, we present data on growth inhibition, molecular mechanisms/biological effects and in vivo antitumour effects of these new RAMBAs against breast cancer cell lines and tumours.…”

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

“…Our RAMBAs, however, based on the retinoid scaffold are considered 'atypical RAMBAs', because they are also endowed with multiple anticancer activities. On the basis of several studies in our lab, it is now evident that the anticancer activities of our RAMBAs cannot be explained by inhibition of ATRA metabolism alone (Patel et al, 2004(Patel et al, , 2007bGediya et al, 2005;Belosay et al, 2006;Huynh et al, 2006). We recently examined the growth inhibitory effects of one of our lead atypical RAMBAs VN/ 66-1 ( Figure 1A) in combination with clinically used suberoylanilide hydroxamic acid (SAHA, a HDACI) on the androgen receptor-positive human prostate LNCaP cell line (Gediya et al, 2005).…”