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Published on: February 6, 2015
Arsenic trioxide exerts synergistic effects with cisplatin on non-small cell lung cancer cells via apoptosis
Hecheng Li1, Xiaoli Zhu, Yawei Zhang
1Department of Thoracic Surgery, Fudan University Cancer Hospital/Cancer Institute, Shanghai, PR China. lihecheng2000@hotmail.com
Background:
Despite multidisciplinary treatment, lung cancer remains a highly lethal disease due to poor response to chemotherapy. The identification of therapeutic agents with synergistic effects with traditional drugs is an alternative for lung cancer therapy. In this study, the synergistic effects of arsenic trioxide (As2O3) with cisplatin (DDP) on A549 and H460 non-small cell lung cancer (NSCLC) cells were explored.
Methods:
A549 and H460 human lung cancer cells were treated with As2O3 and/or DDP. Cell growth curves, cell proliferation, cell cycle, and apoptosis of human cancer cell lines were determined by the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method, clonogenic assay, and flow cytometry (FCM). Apoptosis was further assessed by TUNEL staining. Cell cycle and apoptosis related protein p21, cyclin D1, Bcl-2, bax, clusterin, and caspase-3 were detected by western blot.
Results:
MTT and clonogenic assay showed As2O3 within 10(-2) microM to 10 microM exerted inhibition on the proliferation of NSCLC cells, and 2.5 microM As2O3 exerted synergistic inhibition on proliferation with 3 microg/ml DDP. The combination indices (CI) for A549 and H460 were 0.5 and 0.6, respectively, as confirmed by the synergism of As2O3 with DDP. FCM showed As2O3 did not affect the cell cycle. The G0/G1 fraction ranged from 57% to 62% for controlled A549 cells and cells treated with As2O3 and/or DDP. The G0/G1 fraction ranged from 37% to 42% for controlled H460 cells and cells treated with As2O3 and/or DDP. FCM and TUNEL staining illustrated that the combination of As2O3 and DDP provoked synergistic effects on apoptosis induction based on the analysis of the apoptosis index. Western blotting revealed that the expression of cell cycle related protein p21 and cyclin D1 were not affected by the treatments, whereas apoptosis related protein bax, Bcl-2, and clusterin were significantly regulated by As2O3 and/or DDP treatments compared with controls. The expression of caspase-3 in cells treated with the combination of As2O3 and DDP did not differ from that in cells treated with a single agent.
Conclusion:
As2O3 exerted synergistic effects with DDP on NSCLC cells, and the synergistic effects were partly due to the induction of caspase-independent apoptosis.
Insights
Arsenic trioxide (As2O3) combined with cisplatin (DDP) shows synergistic effects against non-small cell lung cancer (NSCLC) cells. This combination enhances apoptosis, offering a potential new therapeutic strategy for lung cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lung cancer remains a significant cause of mortality due to limited chemotherapy efficacy.
- Investigating synergistic drug combinations is crucial for improving lung cancer treatment outcomes.
Purpose of the Study:
- To explore the synergistic effects of arsenic trioxide (As2O3) and cisplatin (DDP) on non-small cell lung cancer (NSCLC) cell lines.
- To elucidate the mechanisms underlying the combined therapeutic action of As2O3 and DDP.
Main Methods:
- Cell proliferation was assessed using MTT and clonogenic assays.
- Cell cycle distribution and apoptosis were analyzed by flow cytometry (FCM) and TUNEL staining.
- Expression of apoptosis-related proteins (Bcl-2, Bax, clusterin, caspase-3) and cell cycle proteins (p21, cyclin D1) was determined via Western blot.
Main Results:
- As2O3 demonstrated dose-dependent inhibition of NSCLC cell proliferation.
- The combination of As2O3 and DDP exhibited synergistic inhibition of proliferation (Combination Index < 1).
- Combined treatment significantly enhanced apoptosis induction in NSCLC cells, independent of cell cycle effects.
Conclusions:
- As2O3 and DDP display synergistic activity against NSCLC cells.
- The observed synergy is partly mediated by the induction of caspase-independent apoptosis.
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