We here review therapeutic application of a synthetic analog of
retinoids (
vitamin A and its derivatives), named
acyclic retinoid (AR), towards
chemoprevention of
hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected
cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of
lectin-reactive
alpha-fetoprotein (AFP-L3), a marker of occult
cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to
cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous
retinoids and simultaneously is insensitive to
retinoic acid (RA) because of malfunction of its
nuclear receptor,
retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of
extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via
ubiquitin/
proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous
ligand, 9-cis-RA. This may link to both
caspase-dependent and -independent apoptosis of the
cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including
tissue transglutaminase. AR also enhances the sensitivity of HCC cells to
interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these
interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the
chemoprevention of HCC.