Abstract
This study aimed to evaluate the efficacy of cinobufotalin combined with gefitinib in the treatment of lung cancer. A549 cells were treated with gefitinib, cinobufotalin, or cinobufotalin plus gefitinib. MTT assay, annexin-V/PI staining and flow cytometry, TUNEL staining, DCFH-DA staining, Western blot, and real-time RT-PCR were performed to investigate the synergistic inhibitory effect of cinobufotalin combined with gefitinib on the growth of A549 cells. Results showed that cinobufotalin synergized with gefitinib displayed inhibited cell viability and enhanced apoptosis in the combination group. Cinobufotalin combined with gefitinib induced a significant enhancement in reactive oxygen species (ROS) production accompanied by cell cycle arrest in the S phase arrest, characterized by upregulation of p21 and downregulation of cyclin A, cyclin E, and CDK2. Besides, cinobufotalin plus gefitinib downregulated the levels of HGF and c-Met. In summary, cinobufotalin combined with gefitinib impedes viability and facilitates apoptosis of A549 cells, indicating that the combined therapy might be a new promising treatment for lung cancer patients who are resistant to gefitinib.
Highlights
Lung cancer is one of the most typical cancers worldwide, with more than 2 million new cases and over 1.7 million deaths each year [1], of which nonsmall cell lung cancer (NSCLC) accounts for 85% of all lung cancers [2]
E apoptosis rate of A549 cells increased from 4.46% ± 0.65% in control to 14.76% ± 0.48%, 9.34% ± 0.37%, and 44.8% ± 0.62% with treatment of gefitinib 40 μmol/L, cinobufotalin 0.5 mg/mL, and gefitinib plus cinobufotalin, respectively (Figures 2(a) and 2(b))
In Western blot, the expression of Bax and caspase-3 in the A549 cells treated with gefitinib plus cinobufotalin was enhanced, while Bcl-2 expression was significantly downregulated (Figure 2(d))
Summary
Lung cancer is one of the most typical cancers worldwide, with more than 2 million new cases and over 1.7 million deaths each year [1], of which nonsmall cell lung cancer (NSCLC) accounts for 85% of all lung cancers [2]. Toschi et al believed that NSCLC resistance to firstgeneration EGFR-TKIs was related to aberrant cell-mesenchymal epidermal transformation factor (c-Met) activity [8]. Cinobufotalin combined with chemotherapeutic agents has shown potent anticancer effects in a variety of cancers, such as liver cancer, pancreatic cancer, lung cancer, and hepatocellular carcinoma [12]. It has not been determined whether cinobufotalin in combination with gefitinib can be used for the treatment of lung cancer. This study evaluated the efficacy of cinobufotalin combined with gefitinib on the growth of human lung adenocarcinoma A549 cells, providing a new therapeutic therapy for the treatment of NSCLC
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