Retinoids in lung cancer chemoprevention and treatment

Abstract

In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.

Anti-tumor Effects of All-trans Retinoic Acid are Enhanced by Genistein

“…Genistein is an important non-nutrient ingredient in soy and is a specific and potent inhibitor of protein tyrosine kinase [1]. Previous in vitro studies demonstrated that genistein down-regulates expression of several genes including VEGF [15].…”

“…Genistein also possesses an anti-PTK effect [1]; one could speculate that genistein enhances the ATRAinduced tumor cell differentiation and apoptosis via deactivating ERK and JAK/STAT. Angiogenesis is a critical step in the process of cancer progression.…”

“…All-trans retinoic acid (ATRA) is well suitable to induce cell differentiation. There have been attempts to utilize ATRA in prevention and treatment of lung cancer [1]. However, application of large doses of b-carotene, the ATRA precursor, increases the risk of lung carcinogenesis [2].…”

Vitamin A/retinoids signalling in the human lung

“…(D) Early studies have shown that retinoids decreased the incidence of overall second primaries in patients with head and neck cancers [6]. Alltrans retinoic acid (at-RA) was efficient to reverse pre-neoplastic oral lesions and to enhance the regression of cervical intraepithelial neoplasia [7].…”

Growth Inhibition of Refractory Human Gallbladder Cancer Cells by Retinol, and Its Mechanism of Action

“…In particular, the importance of RA is exemplified by its strong cellular differentiation-inducing capability and its utility in the therapy of acute promyelocytic leukemia. [8][9][10] RA also shows anti-proliferative activities against melanoma, 11) prostate cancer, 12,13) lung cancer, 14,15) and breast cancer, 16,17) but not against refractory cancers. None-the less, it is not known whether other forms of vitamin A, such as retinol and REs, in particular retinyl palmitate (RP), exhibit anti-cancer effects.…”