The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers has been limited. In our recent dossier “Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development” we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.

Certain synthetic retinoid-related molecules including the RARgamma-selective compounds CD437 and MX2870-1 and the antagonist MX781, are potent inducers of apoptosis. In this instance however, apoptosis does not require transcription/translation and is independent of the retinoid receptors, although CD437 also induces apoptosis in ovarian carcinoma cells in an RAR-dependent manner. The mechanism by which these molecules induce apoptosis is largely unknown, but activation of stress kinases JNK and p38 by the RARgamma-selective retinoid-related molecules has been shown to be necessary for the release of cytochrome c and subsequent activation of caspases.

Apoptosis stimulators have emerged as key targets for the control of cancer. This therapeutic class has, however, remained predominantly experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. These issues are being addressed as our understanding of the field evolves, and as a result, the identification and exploitation of new targets remains a considerable focus of attention - indeed the number of pro-apoptotic molecules in preclinical development has risen by about 10-fold since 1995.

From a molecular point of view this field has concentrated heavily on the caspases and endogenous inhibitors of apoptosis, predominantly Bcl-2 proteins. Over the past few years a considerable amount of research has been conducted and our view of apoptosis has changed dramatically. Major advances have included the emergence of the IAP ("Inhibitor of Apoptosis Proteins") family.

Further understanding of how retinoid-like molecules stimulate apoptosis is therefore required not to allow optimization of these molecules but also to allow the development of improved stimulators of apoptosis in general. Researchers at Sidney Kimmel Cancer Center, San Diego, have recently published data in the journal Molecular Cancer Therapeutics that address this issue.

Apoptosis can be activated via either the extrinsic or the intrinsic pathway. The latter is triggered by cellular stress and chemotherapeutic drugs which release cytochrome c from mitochondria which binds to a pro-apoptotic protein Apaf-1 resulting in the ATP-dependent oligomerization of Apaf-1 into apoptosomes. Apoptosomes further recruit and activate caspase-9, thus initiating the caspase cascade inducing effector caspases including caspase-3 and eventually culminating in cell death. In an earlier publication Javier Piedrafita and colleagues report that retinoid-like molecules cause the release of cyctochrome c. Having characterized Z-FA-fmk as an inhibitor of caspases 2, -3, -6, and -7. This group proceeded to use this inhibitor to demonstrate that the intrinsic pathway and these down-stream caspases in jurkat T cells mediate the apoptotic effects of MX2870 and MX781.

This study not only characterizes Z-FA-fmk but also elucidates the mechanism of action of retinoids such as MX2870 and MX781. This information should now allow the further optimization of this class of molecule with respect to their pro-apoptotic activity which in combination with independent retinoid receptor mediated effects should lead to the development of highly effective anti-cancer agents.

Entry date Wednesday, April 23, 2003

Adapted from Lopez-Hernandez et al, Mol Cancer Ther. 2003 Mar;2(3):255-63 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk