Xian-Ping Lu

A selective retinoid with high activity against an androgen-resistant prostate cancer cell type

Retinoic acid (RA) and its natural and synthetic analogs, the retinoids, regulate many biological processes, including development, differentiation, cell growth, morphogenesis, metabolism and homeostasis. Retinoid effects are mediated by specific nuclear receptors, the RARs and RXRs. Because of their ability to control cell growth and induce differentiation, retinoids are being examined for the prevention and treatment of several cancers. The majority of retinoids so far analyzed and available inhibit primarily cell proliferation and tumor progression but cannot eliminate cancer cells. In addition, the beneficial effects of the natural retinoids are undermined by undesirable side effects, possibly due to indiscriminate activation of all retinoid receptor subtypes and response pathways. Here, we show that a synthetic retinoid, CD‐271, that activates selectively the RARγ subtype in a given context, shows increased anti‐proliferative activity against certain carcinoma cells over all‐trans‐retinoic acid (tRA). CD‐271 exhibits enhanced activity against DU‐145 prostate adenocarcinoma cells through apoptosis‐inducing activity, while tRA does not. The selective anti‐cancer cell action appears to be receptor‐mediated as an RAR antagonist reverses the inhibition. This profile was not seen with other selective retinoids, such as RARα–selective agonists, anti‐AP‐1 compounds and a non‐apoptosis inducing RARγ agonist. Our data point to a specific role for RARγ in controlling the growth of the prostate, consistent with previous RARγ gene knockout data. The identified retinoid represents a new class of compounds with potential for the treatment of prostate cancer. Int. J. Cancer80:272–278, 1999.

Selective Activation of an Apoptotic Retinoid Precursor in Macrophage Cell Lines

Advances in the understanding of the retinoid signaling mechanism has allowed the discovery of highly selective retinoids that activate only one specific receptor class, subtype, or signaling pathway. These novel compounds lack certain of the common retinoid toxicities and therefore suggest promising new approaches for therapeutic applications. We describe here a new compound, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid methyl ester (MX84), that is selectively activated in macrophages, leading to killing of only macrophage monocyte type cells in vitro. We provide evidence that MX84 is an inactive precursor that is converted into an active apoptosis-inducing retinoid in macrophages. The macrophage activity is also secreted, and our data suggest that the secreted activity is a phospholipase D type activity. Our observation may lead to the development of molecules that are highly macrophage-selective apoptosis inducers in vivo and that could represent important novel therapeutics against diseases caused by excessive macrophage activity.