Retinoids in Cancer Chemoprevention

Masataka      Okuno; Soichi      Kojima; Rie      Matsushima-Nishiwaki; Hisashi      Tsurumi; Yasutoshi      Muto; Scott   L.   Friedman; Hisataka      Moriwaki

Abstract

We review the therapeutic and preventive applications of a retinoid analog (vitamin A and its derivatives) for human cancers. Chemoprevention of cancer is an intervention in the carcinogenic process by chemical agents that block or reverse the malignant transformation of cells. Retinoids are prime candidates for cancer chemoprevention since cancer is characterized by abnormal growth with a lack of differentiation, which could be modified by retinoids. Retinoids exert their biological functions through nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR). A number of experimental and clinical studies have been performed in the past two decades with retinoids showing that they inhibit or reverse the carcinogenic process in some organs, including hematological malignancy as well as premalignant and malignant lesions in the oral cavity, head and neck, breast, skin and liver. We particularly focus upon the therapeutic application of alltrans RA (atRA) to acute promyelocytic leukemia (APL) and on the preventive approach to hepatocellular carcinoma (HCC) by a synthetic retinoid analog, acyclic retinoid. In both malignancies, malfunction of retinoid nuclear receptors is closely related to their carcinogenic process. In APL, a chromosomal translocation produces a chimeric protein between RARα and a protein called promyelocyte leukemia protein (PML). PMLRARα works as a dominant negative receptor in the leukemic cells, interfering with the normal function of RARα and / or PML, which in turn results in the arrest of cell maturation at the stage of promyelocytes. Oral administration of atRA induces differentiation of promyelocytic leukemic cells to mature neutrophils, and leads to a high rates (over 90%) of complete remission. AtRA therapy has become standard in the treatment of APL. In the case of HCC, post-translational modification of RXR by phosphorylation impairs its function, which leads to uncontrolled cell growth. Acyclic retinoid suppresses the phosphorylation of RXR?, restores its function in the presence of its endogenous ligand, 9-cis RA, and thereby induces apoptosis of the cancer cells. Acyclic retinoid given orally successfully suppresses the development of second primary tumors in cirrhotic patients who undergo curative removal of preceding HCC. Eradication of (pre)malignant clones (clonal deletion) from the liver is suggested as a mechanism of the chemopreventive effect. Further development of more effective retinoids as well as their use in combination with other classes of anticancer agents including immunopreventive drugs like interferons may provide strategies for cancer prevention.

Keywords: retinoids, cancer, retinoid analog, retinoid x receptor, promyelocytic leukemia

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