Pirfenidone normalizes the tumor microenvironment to improve chemotherapy

Abstract

// Christiana Polydorou 1, * , Fotios Mpekris 1, * , Panagiotis Papageorgis 1, 2 , Chrysovalantis Voutouri 1 , Triantafyllos Stylianopoulos 1 1 Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus 2 Department of Life Sciences, Program in Biological Sciences, European University Cyprus, Nicosia, Cyprus * These authors contributed equally to this work Correspondence to: Triantafyllos Stylianopoulos, email: tstylian@ucy.ac.cy Keywords: tumor perfusion, vessel compression, breast cancer, drug delivery, biomechanics Received: December 06, 2016 Accepted: February 12, 2017 Published: February 20, 2017 ABSTRACT Normalization of the tumor microenvironment by selectively targeting components of the tumor extracellular matrix has been recently proposed to have the potential to decompress tumor blood vessels, increase vessel perfusion and thus, improve drug delivery and the efficacy of cancer therapy. Therefore, we now need to identify safe and well tolerated pharmaceutical agents that are able to remodel the microenvironment of solid tumors and enhance chemotherapy. In this study, we repurposed Pirfenidone, a clinically approved anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis, to investigate its possible role on tumor microenvironment normalization. Using two orthotopic mammary tumor models we demonstrate that Pirfenidone reduces collagen and hyaluronan levels and, as a result, significantly increases blood vessel functionality and perfusion and improves the anti-tumor efficacy of doxorubicin. Reduction of extracellular matrix components were mediated via TGFβ signaling pathway inhibition due to downregulation of TGFβ1, COL1A1, COL3A1, HAS2, HAS3 expression levels. Our findings provide evidence that repurposing Pirfenidone could be used as a promising strategy to enhance drug delivery to solid tumors by normalizing the tumor microenvironment.