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Synthesis and mechanism of action of novel classes of retinoids and rexinoids with antineoplastic activities

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Action of retinoic acid on cancer cells elucidated

In the search for advanced cancer therapies researchers have investigated the action of retinoic acid (RA). Its impact on cancer cells when combined with other cellular and chemical agents was also observed.

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Trials have shown that retinoids exhibit both preventive and therapeutic action for certain cancers. Aiming to extend on this potential, the European funded project ANTICANCER RETINOIDS researched the anti-cancer action of retinoic acid (RA) and the possibility of combination therapy with other drugs. Dexamethasone and hydrocortisone are steroid hormones which can be used as part of cancer therapy. Dexamethasone for example is given to patients undergoing chemotherapy to counteract certain side effects of the treatment and can be used as an anti-cancer drug in its own right. The project team at the National Cancer Institute in Pordenone in Italy investigated the effects of these two glucocorticoids on Mantle cell lymphoma cells (MCLs). Results were encouraging. Numbers of MCL cells were not significantly increased by physiological concentrations of either steroid. Furthermore, the beneficial antiprolific properties of RA in MCL cells are not affected by either dexamethasone or hydrocortisone. Previous trials had implicated the steroids as promoting increased numbers of Epstein Barr virus immortalised B lymphocytes. Apoptosis through death receptor signalling is one important phenomenon through which cancer can be controlled. The team focused on the TRAIL (Tumour necrosis factor alpha-related apoptosis-inducing ligand) death signalling pathway. The isomer 9-cis-RA was able to sensitise MCL cells to TRAIL dependent apoptosis but without the involvement of TRAIL receptors. Moreover, 9-cis-RNA inhibits the growth promoting effect in MCL cells activated by CD40 (cluster of differentiation 40) cells with or without interleukin-4. It seems then that RA is able to inhibit basal growth of MCL cells as well as antagonising stimulation of their proliferation by external factors such as CD40. These research results have illuminated possibilities for the use of RA isomers both in combination therapy for cancer and exploitation of cross-talk between significant pathways involved. As such, it forms a valuable base for the fight against cancer, one of the major causes of morbidity in Europe.

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