Abstract
Acquired drug resistance constitutes an enormous hurdle in cancer treatment, and the search for effective compounds against resistant cancer is still advancing. Marine organisms are a promising natural resource for the discovery and development of anticancer agents. In this study, we examined whether gliotoxin (GTX), a secondary metabolite isolated from marine-derived Aspergillus fumigatus, inhibits the growth of adriamycin (ADR)-resistant non-small-cell lung cancer (NSCLC) cell lines A549/ADR. We investigated the effects of GTX on A549/ADR cell viability with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the induction of apoptosis in A549/ADR cells treated with GTX via fluorescence-activated cell sorting analysis, Hoechst staining, annexin V/propidium iodide staining, tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, and western blotting. We found that GTX induced apoptosis in A549/ADR cells through the mitochondria-dependent pathway by disrupting mitochondrial membrane potential and activating p53, thereby increasing the expression levels of p21, p53 upregulated modulator of apoptosis (PUMA), Bax, cleaved poly (ADP-ribose) polymerase (PARP), and cleaved caspase-9. More importantly, we discovered that GTX works in conjunction with ADR to exert combinational effects on A549/ADR cells. In conclusion, our results suggest that GTX may have promising effects on ADR-resistant NSCLC cells by inducing mitochondria-dependent apoptosis and through the combined effects of sequential treatment with ADR.
Highlights
Non-small-cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, is one of the world’s leading causes of death, with an incidence of 1.8 million cases and 1.5 million deaths in2012 [1,2]
The two cell lines were observed under a microscope and significant morphological differences were detected between the A549/ADR cell line and the original
0.5 μM ADR did not decrease the proliferation of A549/ADR cells, whereas the viability of A549 cells gradually decreased after 48 h (Figure 1b)
Summary
Non-small-cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, is one of the world’s leading causes of death, with an incidence of 1.8 million cases and 1.5 million deaths in2012 [1,2]. Non-small-cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, is one of the world’s leading causes of death, with an incidence of 1.8 million cases and 1.5 million deaths in. 50% of patients diagnosed with NSCLC present with advanced disease Patients with advanced NSCLC survive for only. One explanation for these discouraging statistics is the development of drug resistance. Chemotherapy resistance has long constituted a major hurdle in the treatment of cancer, especially in NSCLC. This leads to increases in the drug dosage, which in turn increase the cytotoxicity and undesirable effects to normal cells/tissues.
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