Brassinin is an indole-containing phytoalexin reported to have chemopreventative properties. However, the mechanism of action for the anti-cancer activity of brassinin remains unclear. We have identified brassinin as an inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO). IDO modulates immune responses by blocking T cell activation through its ability to catalyze the breakdown of the essential amino acid tryptophan. The physiological relevance of IDO was first established by the demonstration that treatment with the IDO inhibitory compound 1-methyl-tryptophan (1MT) elicits maternal immune rejection of allogeneic mouse concepti. Increased IDO activity has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. We have recently reported that expression of the IDO gene product is negatively regulated by Bin1, an anti-cancer gene that is lost or attenuated during tumor progression [Muller et al., Nature Med 11:312, 2005]. Isogenic tumor grafts lacking Bin1 exhibited markedly enhanced outgrowth, but only in the context of an intact T cell response, and the IDO inhibitor 1MT suppressed the outgrowth of Bin1-null tumors in a T cell-dependent manner. Thus, a major contribution of Bin1 loss to tumorigenesis appears to be through dysregulation of IDO expression and the consequent promotion of anti-tumor immune tolerance. Using 1MT as a proof of principle compound, we have shown that inhibiting the IDO enzyme can leverage the efficacy achieved with cytotoxic chemotherapy in an autochthonous mouse model of breast cancer. We will present evidence that the structurally distinct brassinin molecule can also cooperate with chemotherapy to promote tumor regression and we will discuss the derivatization of brassinin to identify pharmacologically superior IDO inhibitors.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]