Diversity of the intracellular mechanisms underlying the anti-tumor properties of indirubins

Indirubin is a bis-indole isomer of indigo which can be obtained from indigo-producing plants, several species of marine mollusks, several recombinant bacteria and mammalian urine. Indirubin is the active ingredient of a traditional Chinese medicine recipe, Danggui Longhui Wan, reported as a treatment for chronic myelocytic leukemia. Following the discovery of indirubin's interaction with cyclin-dependent kinases, numerous derivatives have been chemically synthesized aiming at the optimization of indirubins' selectivity, solubility and efficacy against tumor growth. Recent studies show that the mechanism of action of indirubins is complex. Additional targets include glycogen synthase kinase-3, c-Src and activation of the Stat3 transcription factor, aryl hydrocarbon receptor, glycogen phosphorylase, and other targets. Interaction with these multiple targets may contribute to the anti-proliferative and cell death inducing effects of indirubins, and avoid the appearance of indirubin-resistant cells.