Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). β-adrenoceptor antagonist drugs (β-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of β-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind β-blockers’ anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed β-blockers’ cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC₅₀ of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with β-agonists, in comparison to the control. This effect might be attributed to β-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR’s multifaceted anticancer properties, implying that combining CAR with β-agonists could be a useful strategy for lung cancer treatment.

Background: From a chemistry point of view, we hypothesized that superlative dual cytotoxicity-radical scavenging bioefficacies of series 4 FQs correlate to their acidic groups and C8-C7 ethylene diamine Chelation Bridge. Methodology: Newly synthesized 16 lipophilic-acid chelating FQs have been screened for in vitro duality of proliferation inhibition and radical scavenging capacities. Results: Substantially in LPS prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of new FQs’ NO scavenging/antiinflammation capacity were 4e<4b<3d<4f<5c0.05). In comparison to classical and robust antineoplastic agent cisplatin and unlike triazoloFQs; nitroFQs (3a, 3b and 3f) and the reduced FQs (4a, 4c, 4d and 4e) exerted antiproliferation IC50 values <50 µM in leukaemia K562. Besides nitroFQ 3, the reduced FQs (4c and 4f) exhibited antineoplastic IC50 values <50 µM in lung A549 carcinoma. NitroFQ 3c and reduced FQs 4b, 4c, and 4f in breast MCF7 and reduced 4c in pancreatic PANC1 had reduction of viability IC50 values <50 µM. NitroFQ 3e, reduced FQs 4b and, 4c and triazoloFQ 5a exerted antiproliferation IC50 values <50 µM in breast T47D cells. Also nitroFQ 3e, reduced FQ 4c and triazoloFQ 5f exhibited antineoplastic IC50 values <50 µM in PC3 prostate cancer cells. Exceptionally triazoloFQ 5a, but neither nitro- nor reduced FQs, had cytotoxicity IC50 value <50 µM in resistant melanoma A375 cells. Unequivocally 4b antineoplastic effectiveness linked with its radical scavenging and antiinflammation effects while 3d and 5c lacked matching antiproliferation potentialities to their exquisite antiinflammation capacities. Explicitly reduced 4e and 4f exerted antiinflammation-selective cytotoxicity duality in vitro. Conclusion: Collectively, this work reveals lipophilic-acidic chelator FQs as authentic agents for the repurposing approach in anticancer chemotherapy/prevention.

Objectives: Fluoroquinolones, such as levofloxacin (LVX), are extended-spectrum drugs used for the treatment of bacterial infections. Several fluoroquinolone derivatives have shown promising antibacterial and anticancer activities. Our group has earlier synthesized and investigated thionated LVX analogs, compounds 2 and 3, on A549 (non-small cell lung cancer) cell line and showed promising anticancer activity. The mechanism of cytotoxicity may be, in part, via aldehyde dehydrogenase enzyme inhibition and antioxidation. In this study, compounds 2 and 3 were evaluated on prostate (PC-3), breast (MCF7), colorectal (Caco-2), and small cell lung cancer (H69 and H69AR) cell lines. Methods: The anticancer activity was measured using resazurin colorimetric method. Combination treatments with doxorubicin (DOX) were also employed and combination index (CI) value were calculated. Results: Compound 3 possessed higher anticancer activity compared to compound 2 on the tested cancer cell lines. Compound 3 had the highest activity on PC-3 cells with IC₅₀ value of 3.58 µM. DOX was also tested for comparison and had IC₅₀ value of less than 0.5 µM in all tested cell lines except for H69AR (DOX-resistant form of H69), which was 4.62 µM. Combination treatment with DOX resulted in significant reduction of cell viability in PC-3, H69, and H69AR cells, with those on H69 and H69AR cells resulted in additive (CI = 1.0) and synergistic effects (CI = 0.6), respectively. Conclusions: Compound 3, a thionated LVX derivative, showed a promising anticancer activity, prompting its potential repurposing for cancer treatment as well as combination treatment with DOX on DOX-resistant cancer cells.