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.

Efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non‐small cell lung cancer: A meta‐analysis

“…Over the past few years, studies have evaluated the efficacy and safety of apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced NSCLC. 7 , 8 However, the results were inconclusive due to the small sample sizes and other mixed factors that affect the treatment response.…”

Apatinib plus docetaxel or pemetrexed shows promising activities against non-small cell lung cancer with brain metastasis: a retrospective analysis

“…Moreover, most of the AEs, such as diarrhea, decreased appetite, fatigue, and HFS, were mild or moderate and could be tolerated ( 27 , 28 ). Since most of our patients had no specific target, such as EGFR mutation or ALK translocation, the amazing efficiency of this regimen was likely exerted by the reasonable combination of pemetrexed or docetaxel ( 29 ), as the single application of either drug had displayed limited or no efficiency, especially for patients with brain metastasis ( 30 ). Originally, apatinib was regarded as an anti-angiogenesis inhibitor against VEGFR-2, similar to drugs of a similar type, namely, sorafenib, sunitinib, and cabozantinib ( 31 ).…”

Apatinib plus chemotherapy is associated with an improved tumor response, survival and tolerance compared with chemotherapy alone for advanced lung adenocarcinoma treatment

“…Furthermore, the present study demonstrated that apatinib plus chemotherapy significantly increased the ORR compared with chemotherapy alone in patients with advanced LUAD. The potential reasons for this are as follows: i) Apatinib may inhibit angiogenesis and tumor growth in LUAD, which would help improve treatment response (25-28); and ii) apatinib may have a synergistic effect with chemotherapy by sensitizing LUAD cells to chemotherapy, thereby enhancing the treatment response (15,29). Survival is also prolonged by apatinib plus chemotherapy in patients with advanced NSCLC, according to previous studies (16,23,30).…”

“…Apatinib is an orally-administered, small-molecule vascular endothelial growth factor receptor-2 inhibitor that suppresses tumor angiogenesis (13). Recent studies have reported the potential benefit of apatinib plus chemotherapy for the treatment of advanced NSCLC (14)(15)(16). For instance, the overall remission rate has been reported to be improved by apatinib plus chemotherapy vs. chemotherapy alone in patients with advanced NSCLC (37 vs. 10%, respectively) (15).…”

“…Recent studies have reported the potential benefit of apatinib plus chemotherapy for the treatment of advanced NSCLC (14)(15)(16). For instance, the overall remission rate has been reported to be improved by apatinib plus chemotherapy vs. chemotherapy alone in patients with advanced NSCLC (37 vs. 10%, respectively) (15). However, evidence for patients with advanced NSCLC carrying negative driver genes is scarce, and only one study has reported that the median progression-free survival (PFS; 5.47 vs. 2.97 months) and disease control rate (DCR; 95 vs. 73%) are increased following second-line apatinib plus chemotherapy compared with chemotherapy alone in patients with advanced NSCLC carrying negative driver genes (16).…”