Abstract
Lung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.
Highlights
Lung cancer is a malignant tumor originating from the bronchial mucosa or lung glands
SiRNA was used to downregulate the expression of Signal transducer and activator of Transcription 3 (STAT3), and the results showed that it inhibited the activation of downstream signals, providing more direct evidence for STAT3 to participate in cell apoptosis
The results demonstrated that the halfmaximal inhibitory concentration (IC50) were significantly rised compare to parental A549 and PC-9 cells, and the resistance index (RI) of A549/GR and PC-9/GR cells were 54.06 and 43.68 (Fig. 1A, B)
Summary
Lung cancer is a malignant tumor originating from the bronchial mucosa or lung glands. The incidence and mortality of lung cancer are increasing. According to statistics from the American Cancer Society, there were 228,150 new cases and 142,670 deaths of lung cancer in America[1]. Among the different types of cancer, lung cancer has been the well-deserved first killer[2]. NSCLC accounts for about 80% of the total lung cancer, and various molecular mechanisms such as gene mutation and abnormal expression have been confirmed to be related to the pathogenesis of NSCLC4. With the continuous development and progress of targeted drug therapy, a variety of molecular targeted therapeutic drugs have been put into clinical use or are undergoing clinical trials. The main targets of lung cancer targeted
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