LZ-106 inhibits anchorage-independent growth of non-small cell lung cancer cells by a positive feedback between reactive oxygen species induction and autophagy flux blockage

Metastasis remains a formidable challenge in the treatment of non-small cell lung Cancer (NSCLC), necessitating novel therapeutic strategies targeting anchorage-independent growth (AIG). This study investigates the inhibitory effects of LZ-106, a Quinolone analog and potential therapeutic candidate for NSCLC, on AIG and metastasis. Through a series of in vitro and in vivo experiments, LZ-106 is demonstrated to induce anoikis in NSCLC cells, inhibiting their AIG ability. Mechanistically, LZ-106 disrupts autophagic flux, leading to the accumulation of autophagosomes and the promotion of anoikis. Additionally, LZ-106 elevates Reactive Oxygen Species (ROS) levels, further enhancing anoikis in NSCLC cells under AIG conditions. Notably, a positive feedback loop between ROS induction and Autophagy flux blockage is identified, reinforcing LZ-106's inhibitory effects on AIG and metastasis. In vivo studies corroborate LZ-106's antimetastatic efficacy, highlighting its potential as a promising therapeutic agent for NSCLC. Together, these findings nominate LZ-106 as a promising antimetastatic candidate and underscore a targetable ROS-autophagy axis for therapeutic development in NSCLC. SIGNIFICANCE STATEMENT: LZ-106 inhibits anchorage-independent growth and metastasis of non-small cell lung Cancer by triggering a positive feedback loop between Reactive Oxygen Species overproduction and autophagic flux blockade, causing autophagosome accumulation and anoikis. In vitro and in vivo data nominate LZ-106 and the reactive oxygen species-autophagy axis as therapeutic targets.