Salinomycin and other polyether ionophores are a new class of anti-scarring agent [Glycobiology and Extracellular Matrices]

December 23rd, 2014 by Woeller, C. F., O'loughlin, C. W., Roztocil, E., Feldon, S. E., Phipps, R. P.

While scarring is a component of wound healing, excessive scar formation is a debilitating condition that results in pain, loss of tissue function and even death. Many tissues including the lung, heart, skin, and eye can develop excessive scar tissue as a result of tissue injury, chronic inflammation or autoimmune disease. Unfortunately, there are few, if any, effective treatments to prevent excess scarring and new treatment strategies are needed. Using HEK293FT cells stably transfected with a TGFβ-dependent luciferase reporter, we performed a small molecule screen to identify novel compounds with anti-scarring activity. We discovered that the polyether ionophore, salinomycin potently inhibited the formation of scar-forming myofibroblasts. Salinomycin (250 nM) blocked TGFβ-dependent expression of the cardinal myofibroblast products alpha smooth muscle actin, calponin and collagen in primary human fibroblasts, without causing cell death. Salinomycin blocked phosphorylation and activation of TAK1 and p38, two proteins fundamentally involved in signaling myofibroblast and scar formation. Expression of constitutively active mitogen activated kinase kinase (MKK) 6, which activates p38 MAPK, attenuated the ability of salinomycin to block myofibroblast formation demonstrating that salinomycin targets the p38 kinase pathway to disrupt TGFβ signaling. These data identify salinomycin and other polyether ionophores as novel potential anti-scarring therapeutics.