Apatinib sensitizes chemoresistant NSCLC cells to doxetaxel via regulating autophagy and enhances the therapeutic efficacy in advanced and refractory/recurrent NSCLC

Abstract

The prognosis of advanced non-small cell lung cancer (NSCLC) is poor; therefore, identifying novel treatment strategies for patients with NSCLC is important. The present study aimed to investigate the efficacy of apatinib plus docetaxel vs. docetaxel alone, as well as their effects on regulating autophagy markers in patients with advanced NSCLC. Furthermore, it was evaluated whether apatinib sensitized chemoresistant NSCLC cells to docetaxel via regulating autophagy. A total of 39 patients with advanced NSCLC were consecutively enrolled and treated with apatinib plus docetaxel (n=19) or docetaxel alone (n=20) for four treatment cycles. The treatment response, adverse events and expression levels of autophagy markers [(light chain 3 α (LC3A) and Beclin-1] were evaluated in tumor samples, which were obtained via biopsy, before treatment and after 2-cycle treatment. In addition, in a mechanistic in vitro experiment, apatinib, docetaxel, the autophagy activator rapamycin and the autophagy inhibitor 3-methyladenine (3-MA) were used to treat docetaxel-resistant A549 (A549/DTX) cells alone or in various combinations. The expression levels of LC3A, Beclin-1, poly (ADP) ribose polymerase (PARP) and phosphorylated (p)-AKT were detected via western blotting, while the cell apoptosis rate was detected with an Annexin V/PI assay. The overall remission rate (37 vs. 10%; P=0.047) and disease control rate (84 vs. 45%; P=0.011) were increased in the Apatinib plus docetaxel group compared with the Docetaxel group. Most of the adverse events were mild and tolerable, and there was no difference between the two groups except for total hypertension and hand-foot syndrome, which were higher in the Apatinib plus docetaxel group). Compared with the levels prior to treatment, Beclin-1 and LC3A remained unchanged post-treatment in the Apatinib plus docetaxel group, while they were increased in the Docetaxel group. Docetaxel increased LC3A, Beclin-1 and p-AKT expression levels, PARP cleavage and the cell apoptosis rate in A549/DTX cells, and rapamycin further enhanced, while 3-MA reduced these effects of docetaxel. Moreover, apatinib repressed LC3A, Beclin-1, p-AKT expression levels and promoted the cell apoptosis rate in A549/DTX cells and docetaxel-treated A549/DTX cells. In conclusion, apatinib synergize the effect of docetaxel in treating patients with advanced NSCLC and chemoresistant NSCLC cells via inhibiting autophagy.