Pirfenidone normalizes the tumor microenvironment to improve chemotherapy

• DOI: 10.18632/oncotarget.15534
• Publication Date: 2017-02-22T16:33:37Z
• Authors: Christiana Polydorou; Fotios Mpekris; Panagiotis Papage...; Chrysovalantis Vo...; Triantafyllos Sty...
• Keywords: collagen; MCF10CA1a cell line; drug tissue level; transforming growth factor beta1; animal cell; Vessel compression; cancer model; Breast cancer; hyaluronan synthase 2; synthetase; Drug Delivery Systems; dose response; hyaluronan synthase 3; hyaluronic acid; Tumor Microenvironment; Biomechanics; transforming growth factor beta; 0303 health sciences; tissue perfusion; gene expression regulation; unclassified drug; 3. Good health; 4T1 cell line; female; drug dose comparison; monotherapy; down regulation; signal transduction; Research Paper; Tumor perfusion; Pyridones; extracellular matrix; animal experiment; Antineoplastic Agents; antineoplastic activity; drug repositioning; doxorubicin; cancer chemotherapy; Article; animal tissue; collagen type 3; 03 medical and health sciences; cancer combination chemotherapy; breast cancer cell line; drug mechanism; tumor microenvironment; Humans; controlled study; human; protein expression; mouse; collagen type 1; blood vessel function; nonhuman; drug potentiation; human cell; animal model; drug efficacy; Drug delivery; pirfenidone

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.