Wang Shunjun, Liu Guowei, Yu Laishun, Zhang Chenzi, Marcucci Fabrizio, Jiang Yupeng
Department of Cardiology Surgery, Xiangya Hospital of Central South University, Changsha, China.
Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China.
Transl Lung Cancer Res. 2024 Nov 30;13(11):3175-3188. doi: 10.21037/tlcr-24-811. Epub 2024 Nov 27.
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.
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.
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).
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.
非小细胞肺癌（NSCLC）是最常见的肺癌亚型，带来了重大的治疗挑战。基于顺铂（CP）的治疗方案是多种实体瘤治疗的核心，但由于其剂量相关的肾毒性，其应用受到限制。我们之前发现氟非尼酮{1-[3-氟苯基]-5-甲基-2-[(1H)]-吡啶酮（AKF-PD）}可有效逆转CP诱导的急性肾损伤（AKI）。然而，尚不清楚AKF-PD与CP联合使用时是否能协同改善NSCLC。因此，本研究旨在探讨AKF-PD对NSCLC的影响，并研究其与CP联合用于癌症治疗的效果。
我们在A549和H1299细胞中进行了细胞活力测定、5-乙炔基-2'-脱氧尿苷（EdU）实验、集落形成测定、伤口愈合试验和Transwell实验，以探究AKF-PD对NSCLC的影响。然后我们检测了上皮-间质转化（EMT）标志物[即上皮钙黏蛋白（E-钙黏蛋白）、基质金属蛋白酶9（MMP9）、波形蛋白和蜗牛家族转录抑制因子1（SNAIL）]、磷脂酰肌醇3-激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素靶蛋白（mTOR）和丝裂原活化蛋白激酶（MAPK），以确定AKF-PD的潜在作用机制。此外，通过联合使用AKF-PD和CP，我们发现AKF-PD增强了CP的抗肿瘤作用，我们认为这可能是由于其对EMT的抑制作用。我们还研究了AKF-PD与CP联合在其他癌细胞系中的作用，包括Hela、SiHA、MDA-MB-231、5-8F和UM-UC-3细胞。
AKF-PD显著抑制NSCLC细胞（A549和H1299）的增殖和侵袭，抑制MAPK和PI3K/AKT/mTOR通路的激活，并抑制肿瘤细胞的EMT。当AKF-PD与CP联合使用时，这些作用进一步增强。我们还发现AKF-PD增强了CP在多种癌细胞系中的抗癌作用，包括宫颈癌（Hela细胞和SiHA细胞）、鼻咽癌（5-8F细胞）、三阴性乳腺癌（MDA-MB-231细胞）和膀胱癌（UM-UC-3细胞）。
AKF-PD不仅减轻CP诱导的AKI，还增强CP的抗癌疗效。我们的研究结果为NSCLC的治疗提供了有价值的见解，可能具有临床应用价值。
