Retinoid metabolism and all-trans retinoic acid-induced growth inhibition in head and neck squamous cell carcinoma cell lines

Abstract

Summary Retinoids can reverse potentially premalignant lesions and prevent second primary tumours in patients with head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been reported that acquired resistance to all-trans retinoic acid (RA) in leukaemia is associated with decreased plasma peak levels, probably the result of enhanced retinoid metabolism. The aim of this study was to investigate the metabolism of retinoids and relate this to growth inhibition in HNSCC. Three HNSCC cell lines were selected on the basis of a large variation in the all-trans RA-induced growth inhibition. Cells were exposed to 9.5 nm (radioactive) for 4 and 24 h, and to 1 and 10 gM (nonradioactive) all-trans RA for 4, 24, 48 and 72 h, and medium and cells were analysed for retinoid metabolites. At all concentrations studied, the amount of growth inhibition was proportional to the extent at which all-trans-, 13-and 9-cis RA disappeared from the medium as well as from the cells. This turnover process coincided with the formation of a group of as yet unidentified polar retinoid metabolites. The level of mRNA of cellular RA-binding protein 11 (CRABP-11), involved in retinoid homeostasis, was inversely proportional to growth inhibition. These findings indicate that for HNSCC retinoid metabolism may be associated with growth inhibition.

Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarian tumour cell line

“…Perhaps cells sensitive to HPR activate, after continuous exposure to the drug, new catabolic pathways in order to protect themselves from the drug growth inhibitory effects. It is interesting to note that in tumour cells, sensitive and naturally resistant to RA, sensisitivity to the growth inhibitory effect of the retinoid was correlated with the ability to metabolize it to polar metabolites (Braakhuis et al, 1997;Van der Leede et al, 1997). The nature and the role of the polar metabolite found in resistant cells are currently being elucidated in our laboratory.…”

4-Hydroxyretinoic Acid, a Novel Substrate for Human Liver Microsomal UDP-glucuronosyltransferase(s) and Recombinant UGT2B7

“…Retinoids are also effective in preventing carcinogenesis and can inhibit proliferation of a large variety of normal and neoplastic cells. In addition, atRA is currently used as a chemotherapeutic agent against promyelocytic leukemia (15), various endothelial cancers (16), breast cancer (17), and endometrial cancer (18). Retinoid metabolism and atRA-induced growth inhibition in head and neck squamous cell carcinoma cell lines has also been documented (16).…”

Identification of Human Cytochrome P450s Involved in the Formation of All-trans-Retinoic Acid Principal Metabolites

“…Metabolism appears to play a key role in the cellular resistance to atRA (Agadir et al, 1995;Kizaki et al, 1996) as well as in the pharmacokinetic resistance seen after several administrations due to an increase in systemic clearance via induced hepatic enzymes (Muindi et al, 1992;Lazzarino et al, 1996). Although the metabolism of atRA has been considered to be a catabolic process, some of its oxidized metabolites have been shown to display biological activity in the modulation of genes expressed in apoptosis, cellular growth and differentiation, embryonic development, and in the inhibition of proliferation of several normal and neoplastic cells in vitro (De Luca, 1991;Reynolds et al, 1993;Ramp et al, 1994;Carter et al, 1996;Braakhuis et al, 1997;Van heusden et al, 1998;Idres et al, 2000). It has also been proposed that atRA metabolism may be linked to its growth inhibitory effects because the most sensitive cell lines are those that metabolize atRA the most efficiently (Takatsuka et al, 1996;.…”