Prodigiosins: a novel family of immunosuppressants with anti-cancer activity.

Prodigiosins (PrGs) are a family of promising therapeutic molecules, isolated mostly from Gram-negative bacteria and characterized by a common pyrryldipyrrylmethene structure with varying side chains. They show a broad spectrum of activities such as anti-microbial, anti-malarial, anti-cancer and immunosuppressive. PrGs are attracting increasing attention due to the ongoing research for less toxic, but effective agents for cancer chemotherapy and immunosuppression for preventing allograft rejection and autoimmunity. Different analogues have been synthesized and evaluated. This review discusses the immunosuppressive and anti-cancer activities of this class of compounds, as both involve inhibition of cell proliferation. The main focus is on the in vitro and in vivo immunosuppressive activity of the different PrGs and the mechanisms involved. PrGs primarily target the T cells, though some effects are observed on other cell types also. Unlike the well-known immunosuppressant cyclosporin A, PrGs do not inhibit the secretion of IL-2 but inhibit the mitogenic signaling from IL-2, suggesting a different mechanism of action. Janus tyrosine kinase 3 (Jak3) that associates with IL-2R upon activation is considered as the molecular target for PrGs. Its restricted expression makes Jak3 as an attractive target for immunosuppressive therapy. However, the available literature suggests that some other pathways are also influenced by the PrGs. These may be important for the anti-cancer activity, as well as immunosuppressive action. Therefore, PrGs appear to be potential candidates for pharmaceutical development as immunosuppressants and also as anti-cancer agents.

Effective prevention of lethal acute graft-versus-host disease by combined immunosuppressive therapy with prodigiosin and cyclosporine A.

Prodigiosin (PDG), a bacterial metabolite, is a known T cell-specific immunosuppressant. Here, we compared its inhibitory potency and mode of action with cyclosporine A (CsA) in a mouse model. PDG efficiently inhibited T cell proliferation with an IC(50) of 3.37 ng/ml, a similar dose to that of CsA (IC(50) of 2.71 ng/ml). PDG inhibited only IL-2Ralpha expression, but not IL-2 expression, whereas CsA inhibited both. Exogenously added IL-2 reversed the suppressive activity of CsA, but not that of PDG. Moreover, although both PDG and CsA markedly reduced mortality rates in lethal acute graft-versus-host disease (GVHD), the combined treatment was more effective than either drug alone. These results demonstrate that PDG and CsA have similar inhibitory potencies, but different modes of action, and suggest that PDG has potential use as a supplementary immunosuppressant in combination with CsA for the treatment of GVHD.