Retinoids have proven to be effective cancer preventive and chemotherapeutic agents. Retinoids can be used to alleviate acute promyelocytic leukemia in humans, leading to an apparent cure when combined with chemotherapy. However, effective retinoids for the treatment of other hematopoietic malignancies are not available yet. Retinoid signals are mediated by the retinoid receptors, RARs and RXRs, which belong to the steroid/thyroid hormone/retinoic acid superfamily of transcription factors. Recent evidences have shown that retinoids can induce apoptosis in certain cancer cell lines. Apoptosis is a naturally occurring form of cell death important for defense, development, homeostasis, and ageing, and alterations in the apoptosis pathways or functions contribute to the pathogenesis of certain human diseases, including cancer. Importantly, a novel class of selective retinoids has been recently discovered which are highly effective against a human non-small cell lung cancer in an animal model. These retinoids can induce apoptosis in certain cell lines, including several leukemia cell lines, and show promise as novel direct therapeutic agents for the treatment of cancer.
They aim to investigate the mechanisms of action of these novel apoptosis inducing retinoids in leukemia cells. They will analyze the potential role of two transcription factors, Sp1 and NfkB, in retinoid-induce apoptosis. They have found that treatment of leukemia cell lines with those apoptotic retinoids causes loss of the DNA binding activity of both transcription factors: Sp1 is a target for caspases, while NfkB is translocated into the cytosol. They provide evidence that activation of caspases in necessary for retinoid-induced apoptosis. This is partially affected by inhibitors of protein synthesis. However, inhibition of RNA transcription has no effect on retinoid-induced apoptosis, suggesting a new mechanism of action for those novel retinoids which is independent of transcription. Thus, understanding the role of Sp1 cleavage and the mechanism of NfkB inhibition during retinoid-induced apoptosis will significantly enhance their knowledge of this novel retinoid action, and is likely to refine the future design and improve the development of new retinoids which would result in more effective treatments of leukemia.
