Thalidomide and its analogs: a potential immunomodulatory alternative for treating liver diseases and cirrhosis
Fernández Martínez, Tomas Eduardo
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Thalidomide is currently used for treating erythema nodosum leprosum, multiple myeloma, angiogenesis, rheumatoid arthritis, graft-versus-host disease, among others. Thalidomide effects are related to its capacity to inhibit the proinflammatory cytokine tumor necrosis factor-? (TNF-?) and, in consequence, causes immunomodulation on other cytokines. During the establishment of some diseases the balance between proinflammatory and antiinflammatory cytokines is disrupted, promoting a pathological state; thus, elevated levels of proinflammatory cytokines mediate several deleterious processes such as inflammation, necrosis, apoptosis and fibrosis. These events are present in acute and chronic degenerative liver diseases such as hepatitis, cholangitis, cirrhosis and hepatocellular carcinoma (HCC). Then, the immunomodulation on cytokines by drugs seems to be a pharmacological target to ameliorate liver damage and cirrhosis. In fact, there are not sufficient drugs for relief or cure of cirrhosis currently; some of these few are expensive, unstable and palliative or may cause side effects. Novel thalidomide analogs have been synthesized with improved stability and potency as TNF-? inhibitory and immunomodulatory agents, besides low or none teratogenicity. Experimental assessment of thalidomide and its analogs in animal models of liver injury have afforded very hopeful outcomes. Thalidomide and two analogs have evidenced anticholestatic, antinecrotic and antifibrotic activities in bile duct ligation-induced biliary cirrhosis. Another analog protected D-galactosamine/endotoxin-treated mice from liver damage. Thalidomide ameliorated the alcoholic hepatic injury and prevented necrosis, cholestasis and fibrosis induced by CCl4 in rats. Moreover, this drug salvaged from lethal hepatic necroinflammation and accelerated the recovery from established thioacetamide-provoked cirrhosis in rats. The antiinflammatory, antinecrotic and antifibrotic effects elicited by thalidomide and its analogs are mainly mediated by the inhibition on TNF-? through two different routes, as well as the down-regulation of nuclear factor-?B (NF-?B) signaling pathway and by diminishing adhesion molecules to prevent the progression of liver fibrosis and cirrhosis. Furthermore, thalidomide showed beneficial effects on HCC by decreasing angiogenesis and metastasis in murine models; therefore, diverse clinical phase I/II studies were carried out to evaluate its antitumoral or disease control outcomes. However, thalidomide as a single drug therapy yields very modest benefits, although in most cases this is well tolerated and offers disease stabilization. Different doses and the combination with other chemotherapeutic agents appear to enhance therapeutic effects; the assessment of the new thalidomide analogs in next clinical trials of HCC healing is strongly suggested. Thalidomide and its analogs may be a feasible option for the treatment of liver diseases and cirrhosis.