3-Formylchromone attenuates urethane-induced lung carcinogenesis and enhances gefitinib anti-tumor response via modulation of IL-6/JAK1/STAT3/cyclin D1 signaling

Lung cancer is the primary cause of cancer-related mortality globally. The reduced sensitivity to tyrosine kinase inhibitors (TKIs) upon prolonged treatment necessitates the search for effective modalities to improve the management of lung cancer. This study investigates the potential anti-tumor effect of 3-formylchromone against lung cancer and its possible modulatory effect on the response to the TKI gefitinib. In vitro cytotoxicity evaluation of the investigated agents was carried out using MTT assay. In addition, the in vivo model of urethane-induced lung cancer in BALB/c mice was applied to evaluate the anti-tumor effect of 3-formylchromone alone and upon combination with gefitinib. MTT assay confirmed the cytotoxic effects of 3-formylchromone and gefitinib against human A549 cells, with gefitinib exhibiting a significantly lower IC50 compared to 3-formylchromone. Results of the in vivo model revealed a significant down-regulation of IL-6 content in the lung, repressed phosphorylation and activation of JAK1/STAT3 signaling, and declined protein expression of the proliferation marker cyclin D1 by 3-formylchromone treatment, relative to urethane group. 3-Formylchromone/gefitinib combination therapy further improved the therapeutic management of lung cancer with markedly reduced number/size of tumor nodules and the pathological changes in the lung, along with the powerful interference with IL-6/JAK1/STAT3 signaling, relative to gefitinib-treated group. Collectively, 3-formylchromone exhibits anti-tumor effect and could enhance gefitinib efficacy against lung cancer, at least partly, through inhibition of IL-6/JAK1/STAT3/cyclin D1 signaling. Thus, it can be suggested as a promising modality to investigate the potential to improve the management of lung cancer and to overcome the reduced sensitivity to gefitinib on prolonged therapy.