Differential Effects of Synthetic Nuclear Retinoid Receptor-selective Retinoids on the Growth of Human Non-Small Cell Lung Carcinoma Cells

Abstract

Retinoids are promising agents for cancer chemoprevention and therapy. Nuclear retinoic acid receptors (RARs; RARα, -β, and -γ) and retinoid X receptors (RXRs; RXRα, -β, and -γ) are thought to mediate most of retinoids' effects on cell growth and differentiation. Because the majority of human non-small cell lung carcinoma (NSCLC) cell lines are resistant to all-trans-retinoic acid, we searched for more potent retinoids. Therefore, we examined the effects of 37 natural and synthetic retinoids that exhibit specific binding to and transactivation of individual RARs or RXRs on the proliferation of eight human NSCLC cell lines. All of these cells expressed mRNAs of the three RXRs; however, they expressed varying levels of RARα and RARγ, and only three of the eight cell lines expressed RARβ mRNA. Cellular retinoic acid-binding proteins (CRABPs) I and II were detected in one and three of the eight cell lines, respectively. Only 8 of the 37 retinoids exhibited growth-inhibitory activity (IC₅₀, <10 µm) against at least two of the eight NSCLC cell lines. The active retinoids included one (TD550) of five RARα-selective, one (Ch55) of three RARβ-selective, three (CD437, CD2325, and SR11364) of six RARγ-selective, and one (CD271) of four RARβ/γ-selective retinoids. The potency of these retinoids was low (IC₅₀, >1 µm), except for CD437, which was very potent (IC₅₀, 0.1–0.5 µm). The six RXR-selective retinoids were mostly inactive even at 10 µm. However, combinations of RAR-selective and RXR-selective retinoids exhibited additive effects. There appeared to be no simple correlation among the histological type of the NSCLC (adeno- or squamous), the levels of nuclear receptors or CRABPs, and the response of the cells to the growth-inhibitory effects of retinoids. Nevertheless, in contrast with former studies with natural retinoids, these results suggest that several synthetic retinoids do exhibit inhibitory activity against NSCLC cells, and some of them may be useful clinically.