Halofuginone for fibrosis, regeneration and cancer in the gastrointestinal tract

Abstract

Organ fibrosis and architectural remodeling can severely disrupt tissue function, often with fatal consequences. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli, and the key cellular mediator of fibrosis comprises the myofibroblasts which, when activated, serve as the primary collagen-producing cells. Complex links exist between fibrosis, regeneration and carcinogenesis, and the concept that all organs contain common tissue fibrosis pathways that could be potential therapeutic targets is an attractive one. Because of the major impact of fibrosis on human health there is an unmet need for safe and effective therapies that directly target fibrosis. Halofuginone inhibits tissue fibrosis and regeneration, and thereby affects the development of tumors in various tissues along the gastrointestinal tract. The high efficacy of halofuginone in reducing the fibrosis that affects tumor growth and tissue regeneration is probably due to its dual role in inhibiting the signaling pathway of transforming growth factor β, on the one hand, and inhibiting the development of Th17 cells, on the other hand. At present halofuginone is being evaluated in a clinical trial for other fibrotic indication, and any clinical success in that trial would allow the use of halofuginone, also for all other fibrotic indications, including those of the gastrointestinal tract.

Keywords: Cancer; Extracellular matrix; Myofibroblast; Stellate cell; Transforming growth factor β.

Figure 1

Halofuginone mode of action. Two pathways have been suggested for the biological activity of halofuginone which may be connected. In fibrosis and in cancer (left side) the tumor growth factor (TGF) β derived from the inflammatory cells binds to the constitutively active type II TGFβ receptor kinase that trans-phosphorylates the type I receptor. Activated type I receptor kinase then phosphorylates Smads 2/3, which subsequently recruit Smad4. The activated Smads 2/3 Smad4 complex then translocates to the nucleus where it regulates specific gene expression. The TGFβ -dependent gene expression causes quiescent fibroblasts differentiation to myofibroblasts, which are responsible for the major increase in matrix synthesis in fibrosis and in tumor stroma which impedes normal function. Halofuginone inhibited TGFβ-dependent Smad3 phosphorylation, causes reduction in fibroblasts differentiation, reduction in the levels of extracellular matrix (ECM) proteins and inhibition of fibrosis and tumor growth. Recently, a second mechanism has been suggested for the halofuginone- dependent inhibition of autoimmune diseases which involves selective prevention of the development of Th17 cells by activating the amino acid starvation response (AAR) - the amino acid starvation response (right side). Naïve CD4⁺ T cells differentiate into diverse effector and regulatory subsets to coordinate immunity to pathogens while establishing peripheral tolerance. Besides T_H1 and T_H2 effector subsets, naïve T cells can differentiate into proinflammatory T helper 17 (T_H17) cells. These cells are key regulators of autoimmune inflammation. The mechanism by which halofuginone inhibits the AAR is by binding to glutamyl-prolyl-tRNA synthetase (EPRS) and inhibiting prolyl-tRNA synthetase activity (ProRS) causing intracellular accumulation of uncharged tRNA and mimicking reduced cellular proline availability. AAR activation selectively inhibits T_H17 differentiation. Thus, halofuginone could potentially be used to address any autoimmune or inflammatory disease associated with Th17 cells. It should be noted (middle) that TGFβ is required for facilitation of differentiation of the inflammatory Th17 cell subset which suggests the existence of a link between the TGFβ and AAR pathways.