Novel retinoid-related molecules as apoptosis inducers and effectve inhibitors of human lung cancer cells in vivo

Abstract

Lung cancer causes more than 140,000 deaths annually in the United States alone, and the prognosis for non-small cell lung cancer (NSCLC) is particularly poor¹. Therapies using small molecules that preferentially kill lung tumor cells by inducing cellular suicide (apoptosis) would therefore be highly desirable. Retinoids have shown promise as cancer preventive and cancer therapeutic agents^2–5. Retinoid signals are mediated by two classes of nuclear receptors: the retinoic acid receptors (RARα, β, and γ) and the retinoid X receptors (RXRα, β and γ)^5–8. These receptors usually bind as heterodimers to specific DNA sequences⁹ and/or interact with other transcriptional regulators, such as AP-1 (ref. 10) to regulate gene transcription. Synthetic retinoids can be made that activate only specific portions of the complex retinoid response network^11–15 and activate selective biological programs. To identify retinoids with novel biological activities, we used a high-throughput “biological activity fingerprint” screen on a large library of retinoids and retinoid-related molecules (RRMs). We identified new structures that are highly effective against lung cancer cells in vitro, inducing apoptosis. We show here for one of these compounds that it is very effective against a human NSCLC in vivo in an animal model. These new molecules show a distinct pattern of receptor signaling.