Differential responses of normal, premalignant, and malignant human bronchial epithelial cells to receptor-selective retinoids

Using an in vitro lung carcinogenesis model consisting of normal, premalign ant, and malignant human bronchial epithelial (HBE) cells, we analyzed the growth inhibitory effects of 26 novel synthetic retinoic acid receptor (RAR )- and retinoid X receptor (RXR)-selective retinoids. RAR-selective retinoi ds such as CD271, CD437, CD2325, and SR11364 showed potent activity in inhi biting the growth of either normal or premalignant and malignant HBE cells (IC50S mostly <1 mu M) and were much more potent than RXR-selective retinoi ds, Nonetheless, the combination of RAR- and RXR-selective retinoids exhibi ted additive effects in HBE cells. As the HBE cells became progressively mo re malignant, they exhibited decreased or lost sensitivity to many retinoid s. The activity of the RAR-selective retinoids, with the exception of the m ost potent retinoid, CD437, could he suppressed by an RAR panantagonist, Th ese results suggest that: (a) RAR/RXR heterodimers play an important role i n mediating the growth inhibitory effects of most retinoids in HBE cells; ( b) CD437 may act through an RAR-independent pathway; (c) some of the RAR-se lective retinoids may have the potential to be used in the clinic as chemop reventive and chemotherapeutic agents for lung cancer; and (d) early stages of lung carcinogenesis may be responsive targets for chemoprevention by re tinoids, as opposed to later stages.