Fluorofenidone enhances cisplatin efficacy in non-small cell lung cancer: a novel approach to inhibiting cancer progression

Background: Non-small cell lung Cancer (NSCLC), the most prevalent lung Cancer subtype, presents significant treatment challenges. Cisplatin (CP)-based regimens are central to the treatment of multiple solid tumors, but its use is restricted due to its dose-related renal toxicity. We previously found that fluorofenidone {1-[3-fluorophenyl]-5-methyl-2-[(1H)]-pyridone (AKF-PD)} effectively reverses CP-induced acute kidney injury (AKI). However, it remains unclear whether AKF-PD can synergistically ameliorate NSCLC when used together with CP. Thus, this study sought to investigate the effect of AKF-PD on NSCLC and examined its combinatory use with CP for Cancer treatment.

Methods: We conducted cell viability assays, 5-ethynyl-2'-deoxyuridine (EdU) experiments, colony-forming assays, wound-healing tests, and Transwell experiments in A549 and H1299 cells to explore the effects of AKF-PD on NSCLC. We then detected the epithelial-mesenchymal transition (EMT) markers [i.e., epithelial Cadherin (E-cadherin), matrix metallopeptidase 9 (MMP9), vimentin, and snail family transcriptional repressor 1 (SNAIL)], phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK), to identify the potential mechanisms of AKF-PD. Further, via the combined use of AKF-PD and CP, we found that AKF-PD enhanced the antitumor effect of CP, and we suggest that this may be due to its inhibitory effect on EMT. We also examined the effect of combining AKF-PD and CP in other Cancer cell lines, including Hela, SiHA, MDA-MB-231, 5-8F, and UM-UC-3 cells.

Results: AKF-PD significantly inhibited the proliferation and invasion of NSCLC cells (A549 and H1299), suppressed the activation of the MAPK and PI3K/Akt/mTOR pathways, and inhibited the EMT of the tumor cells. When AKF-PD was used in combination with CP, these effects were further enhanced. We also found that AKF-PD enhanced the anti-cancer effect of CP in a variety of Cancer cell lines, including cervical Cancer (Hela cells and SiHA cells), nasopharyngeal Cancer (5-8F cells), triple-negative breast Cancer (MDA-MB-231 cells), and bladder Cancer (UM-UC-3 cells).

Conclusions: AKF-PD not only mitigates CP-induced AKI but also enhances the anti-cancer efficacy of CP. Our findings provide valuable insights into the treatment of NSCLC and may have clinical applications.

Non-small cell lung cancer (NSCLC); cisplatin (CP); epithelial-mesenchymal transition (EMT); fluorofenidone (AKF-PD).