Abstract
BackgroundAnti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis. Because activated fibroblasts in inflammatory conditions have similar characteristics as cancer-associated fibroblasts (CAFs) and CAFs contribute actively to the malignant phenotype, we believe that anti-fibrotic drugs have the potential to be repurposed as anti-cancer drugs.MethodsThe effects of pirfenidone alone and in combination with cisplatin on human patient-derived CAF cell lines and non-small cell lung cancer (NSCLC) cell lines were examined. The impact on cell death in vitro as well as tumor growth in a mouse model was determined. Annexin V/PI staining and Western blot analysis were used to characterize cell death. Synergy was assessed with the combination index method using Calcusyn software.ResultsPirfenidone alone induced apoptotic cell death in lung CAFs at a high concentration (1.5 mg/mL). However, co-culture in vitro experiments and co-implantation in vivo experiments showed that the combination of low doses of cisplatin (10 μM) and low doses of pirfenidone (0.5 mg/mL), in both CAFs and tumors, lead to increased cell death and decreased tumor progression, respectively. Furthermore, the combination of cisplatin and pirfenidone in NSCLC cells (A549 and H157 cells) leads to increased apoptosis and synergistic cell death.ConclusionsOur studies reveal for the first time that the combination of cisplatin and pirfenidone is active in preclinical models of NSCLC and therefore may be a new therapeutic approach in this disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2162-z) contains supplementary material, which is available to authorized users.
Highlights
Anti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis
We demonstrated that the combination of pirfenidone and cisplatin suppressed the proliferation of non-small cell lung cancer (NSCLC) cells and cancer-associated fibroblasts (CAFs)
These results suggest that high concentration of pirfenidone cause the activation of the apoptotic pathway in lung CAFs leading to cell death
Summary
Anti-fibrotic drugs such as pirfenidone have been developed for the treatment of idiopathic pulmonary fibrosis. The tumor microenvironment or tumor stroma comprises various cell types, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and mesenchymal cells In this heterogeneous environment, CAFs are the most prominent cell type and are known to be key contributors to tumor progression, invasion, and metastasis [1]. CAFs are the most prominent cell type and are known to be key contributors to tumor progression, invasion, and metastasis [1] Functionally, they are known to secrete extracellular matrix proteins (e.g., collagen I, III, IV), chemokines (e.g., interleukin 6, CXCL8, CXCL12), cytokines (e.g., interleukin 6 and interleukin 8), and tumor growth factors (e.g., vascular endothelial-derived growth factor, transforming growth factor beta (TGFβ), hepatocyte growth factor, epidermal growth factor, and fibroblast growth factor] [2, 3]. A combined therapy that targets both the tumor cell and the CAFs might lead to novel therapies in cancer
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