Targeting TGFβ signaling to inhibit fibroblast activation as a therapy for fibrosis and cancer: effect of halofuginone.

The fibroblast to myofibroblast transition in wound healing, fibrosis and cancer has emerged as a viable target for pharmacological intervention. The myofibroblasts acquire specific characteristics because of differences in origin and localization, but also share common properties, such as TGFβ signaling. Halofuginone, an inhibitor of the Smad3 phosphorylation, downstream of the TGFβ signaling, inhibits the activation of fibroblasts and their ability to synthesize the extracellular matrix, regardless of their origin or location. Halofuginone prevented the new and stimulated resolution of pre-existing fibrosis of several organs and inhibited the development and progression of various tumors. Moreover, halofuginone synergizes with chemotherapy and reduces the need for high doses of toxic compounds without impairing the treatment efficacy. In fibrosis, where the myofibroblasts are the major participant, halofuginone can be used as a single therapy, whereas in cancer it should be considered in combination with other therapies that affect the tumor cells via different modalities.