Abstract
BackgroundDespite 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.MethodsA549 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.ResultsMTT and clonogenic assay showed As2O3 within 10-2 μM to 10 μM exerted inhibition on the proliferation of NSCLC cells, and 2.5 μM As2O3 exerted synergistic inhibition on proliferation with 3 μg/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.ConclusionAs2O3 exerted synergistic effects with DDP on NSCLC cells, and the synergistic effects were partly due to the induction of caspase-independent apoptosis.
Highlights
Despite multidisciplinary treatment, lung cancer remains a highly lethal disease due to poor response to chemotherapy
As2O3 exerted synergistic effects with DDP on non-small cell lung cancer (NSCLC) cells, and the synergistic effects were partly due to the induction of caspase-independent apoptosis
Recent evidence indicates that arsenic trioxide (As2O3) may induce clinical remission in patients with acute promyelocytic leukemia (APL), and several investigations show that As2O3 induced programmed cell death in APL cell lines [2,3,4,5]
Summary
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. The synergistic effects of arsenic trioxide (As2O3) with cisplatin (DDP) on A549 and H460 non-small cell lung cancer (NSCLC) cells were explored. The identification of new therapeutic agents that exert synergistic effects in combination with traditional cytotoxic agents is an alternative strategy for the systemic treatment of lung cancer. Due to the poor therapeutic effects of current cytotoxic-agents on lung cancer, the ability of As2O3 to induce apoptosis in non-small cell lung cancer cells was explored in the present study, and the synergistic effects of As2O3 with DDP on A549 and H460 lung cancer cells were analyzed
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