The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells

Abstract

SummaryThe clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozolefumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10-6 M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (1 06 M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (1 0-6 M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity.

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

“…This is in line with earlier studies suggesting that VAD is associated with carcinogenesis (Wolbach and Howe, 1925), and upregulation of CYP26A1 has recently been shown in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). If increased RA metabolism is solely responsible for the apoptogen desensitizing effect, our results would imply that in a state of RA deficiency, cells may be less susceptible to apoptosis following the acquisition of DNA damage.…”

“…Despite the fact that the CYP26 enzymes may have a similar but separate role in limiting the consequences of fluctuations in nutritional vitamin A, the possibility that pathological conditions such as cancer might involve aberrant expression of CYP26A1 has recently emerged from several studies. Accumulating evidence has shown that enhanced RA catabolic activity has been observed in various types of cancer and elevated CYP26A1 expression has been detected in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). On the other hand, our previous study has shown that the cells expressing CYP26A1 gain significant resistance to apoptosis because of the state of reduced bioavailability caused by the metabolic inactivation of RA (Osanai and Petkovich, 2005).…”

“…Several investigators have revealed that deregulated overexpression of CYP26A1 could be detected in a number of cancer cell types, including breast carcinomas (Sonneveld et al, 1998;Van heusden et al, 1998). First, we investigated the expression of CYP26A1 in breast cancers with tissue microarray slides.…”

Inhibition of all-TRANS-retinoic acid metabolism by R116010 induces antitumour activity

“…After centrifugation for 10 min at 780 g, the supernatant was analyzed for the presence of RA metabolites. Reverse-phase HPLC analysis was carried out as described previously (Van heusden et al, 1998).…”

“…In vitro, liarozole-fumarate has been shown to enhance both the antiproliferative and differentiation-inducing activity of RA (Wouters et al, 1992;Van heusden et al, 1996Van heusden et al, , 1998. In vivo, liarozole-fumarate increases endogenous RA levels both in plasma and tissues (Smets et al, 1995).…”