Preclinical studies on the antitumor and non‐toxic effect of combining pirfenidone with vinorelbine and carboplatin in non‐small cell lung cancer

Non-small cell lung cancer (NSCLC) shows limited therapeutic response to vinorelbine and carboplatin. Combining these drugs with an antifibrotic drug may enhance their antitumor effect. Pirfenidone is an antifibrotic drug whose antitumor activity has been described in different types of cancer. This work aimed to perform preclinical studies on the combination of pirfenidone with vinorelbine, or with vinorelbine plus carboplatin, in NSCLC. Our data revealed that pirfenidone sensitized three NSCLC cell lines to vinorelbine by reducing cell growth, viability and proliferation, inducing alterations in the cell cycle profile, and increasing cell death (%). Importantly, pirfenidone increased the sensitivity of the three NSCLC cell lines to the combined treatment of vinorelbine plus carboplatin. This combined drug treatment (triplet) did not induce cytotoxicity against non-tumorigenic cells. Notably, the triplet drug combination significantly reduced the growth and proliferation of A-549 xenografts in nude mice, as also reduced vimentin and collagen expression. Most interestingly, the triplet treatment exhibited a safer toxicological profile than the doublet (vinorelbine plus carboplatin) currently applied in the clinical practice. Altogether, these preclinical data support the possibility of repurposing pirfenidone in combination with vinorelbine or with vinorelbine plus carboplatin for NSCLC perioperative treatment, improving therapeutic efficacy while reducing toxicity.