The PCNA inhibitor AOH1996 impairs tumor growth and invasiveness in non–small cell lung cancer

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Background Lung cancer (LC) is the leading cause of cancer-related deaths worldwide, with a 5-year survival rate of less than 10% in advanced or metastatic disease. AOH1996 is a novel small molecule inhibitor of cancer-associated Proliferating Cell Nuclear Antigen (PCNA). It disrupts DNA replication and repair by enhancing PCNA-RPB1 interactions, dissociating PCNA from transcribed chromatin, and inducing DNA double-strand breaks (DSBs), resulting in selective toxicity of various cancer types. The anticancer effects of AOH1996 on LC remain unclear. Methods In this study, the anticancer effect of AOH1996 was first examined on four non-small cell lung cancer (NSCLC) cells, namely, A549, LNM35, NCI-H358, and NCI-H460 cell lines using cellular viability assay. Subsequent in vitro assays, including colony growth, migration and invasion assays in addition to tumor growth using chick embryo chorioallantoic membrane (CAM) assay in vivo were conducted on A549 and LNM35 cells. The underlying molecular mechanism has been investigated using western blots. Results We demonstrated that AOH1996 significantly decreased NSCLC cells viability and colony growth in vitro in a concentration- and time-dependent manner. AOH1996 also suppressed their tumor growth in the chick embryo CAM xenograft model in vivo without causing toxicity. Moreover, AOH1996 reduced A549 and LNM35 cell migration and invasion in vitro . Mechanistically, AOH1996 induced cellular DNA damage, as evidenced by increased γH2AX levels. It also upregulated p53 and its downstream p21 along with activating caspase-3/7 and PARP cleavage. Conclusion Our findings highlight AOH1996 as a promising therapeutic agent for NSCLC management, with potent effects on cell survival, migration, invasion, and tumour growth.

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