A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC₅₀ values in the submicromolar–micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation.

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDD_L) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD_S) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDD_L, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDD_S, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDD_S-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD_L or CDD_S in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death. Although molecular stratification and multimodal therapy have improved outcomes in selected patients, overall prognosis is still limited by late diagnosis, heterogeneity, and treatment resistance. Immune checkpoint inhibitors (ICIs) have substantially improved survival outcomes in a subset of patients; however, the overall benefit remains limited, and both primary and acquired resistance are common. Neutrophils, as key effectors of innate immune responses, can be activated by diverse stimuli and release neutrophil extracellular traps (NETs). Growing evidence indicates that neutrophils and NETs contribute to remodeling of the tumor microenvironment (TME) in NSCLC, promoting resistance to ICIs. This review systematically summarizes the biological features, key molecular pathways, and inducing factors of neutrophils and NETs in lung cancer and synthesizes evidence supporting their roles as biomarkers of ICI efficacy and prognosis. We further focus on the mechanisms by which NETs mediate immunosuppression and foster an immune-excluded TME, thereby driving resistance to immunotherapy. In addition, we outline potential therapeutic and combination strategies targeting neutrophils and NETs, providing a theoretical basis for developing optimized immunotherapy approaches for NSCLC that target neutrophils and NETs.

Resistance to many chemotherapeutic drugs is caused by resistance to induction of apoptosis. TRAIL (TNF-related apoptosis-inducing ligand) selectively triggers apoptosis in cancer cells, but is subject to resistance as well. Combinations may bypass resistance and enhance TRAIL-based therapies. This study investigates whether the HSP90 inhibitor 17-AAG can enhance TRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) cells, either relatively sensitive (H460) or resistant (A549) to TRAIL. Growth inhibition and cell death were assessed using MTT (methyl thiazole tetrazolium) and annexin/propidium iodide assays. Cell cycle analysis was conducted via flow cytometry, and cell death mechanisms were explored with Western blotting. Targeting HSP90 with 17-AAG effectively increased TRAIL-induced apoptosis in H460 cells and reversed resistance to the TRAIL-resistant A549 cells. The significantly enhanced TRAIL-induced apoptosis was mediated through the activation of caspases, particularly caspase-8, while in TRAIL-resistant A549 cells, 17-AAG reinstated apoptosis by cleaving RIPK1, thus preventing RIPK1-dependent survival signaling. Notably, 17-AAG also suppressed Akt activity, a known regulator of TRAIL activity; moreover, inhibition of PI3K by LY294002 sensitized cells to TRAIL-induced apoptosis. These findings suggest that HSP90 inhibitors combined with TRAIL receptor agonists might be of therapeutic value for the treatment of NSCLC.