Apatinib has anti-tumor effects and induces autophagy in colon cancer cells

Document Type : Original Article


1 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei province, China

2 Hubei Key laboratory of Digestive System, Renmin Hospital of Wuhan University, Wuhan, China

3 Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China

4 Jiangsu Hengrui Medicine Co, Ltd, Lian yungang, 222047, China


Objective(s): Apatinib recently has been used to treat patients with gastric cancer, but the function of apatinib in colon cancer remains unclear. This study was conducted to investigate the impacts of apatinib on the biological function and its potential mechanism of colon cancer cells in vitro.
Materials and Methods:The effect of apatinib in colon cancer cells were detected by assessing cell viability, migration and invasion capabilities. Apoptosis cells and the cell cycle distribution of colon cancer cells were analyzed by flow cytometry. The potential mechanism was investigated via autophagy related proteins and pathways in vitro.
Results: The proliferation, migration and invasion of colon cancer cells were inhibited when they were treated with different concentration of apatinib (20, 40 μM). When HCT116 and SW480 cells were treated with apatinib at the concentration of 20 μM, the apoptosis percentage were 3.7% and 5.8% respectively. As the drug concentration increased to 40μΜ, the the apoptosis percentage increased to 11.9% and 13.5%. Meanwhile, cell cycle was also altered. Furthermore, apatinib inhibited the expression of AKT-mTOR signaling pathway and increased the expression of LC3-Ⅱ.
Conclusion: Apatinib can significantly inhibit the malignant phenotype of colon cancer cells, and it was involved in regulation of autophagy.


1. Brenner H, Kloor M, Pox CP. Colorectal cancer.  Lancet 2014; 383:1437.
2. bParkin DM. Global cancer statistics in the year 2000.  Lancet Oncol 2001; 2:533-543.
3. Gill S, Thomas RR, Goldberg RM. Colorectal cancer chemotherapy. Aliment Pharmacol Ther 2003; 18:683-692.
4. Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2016; 22:6876-6889.
5. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 2003; 10:159-165.
6. Chatterjee S, Heukamp LC, Siobal M, Schottle J, Wieczorek C, Peifer M, et al. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest 2013; 123:1732-1740.
7. Fontanella C, Ongaro E, Bolzonello S, Guardascione M, Fasola G, Aprile G. Clinical advances in the development of novel VEGFR2 inhibitors. Ann Translat Med 2014; 2:123.
8. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions.  Lancet  2016; 388:518-529.
9. Roviello G, Ravelli A, Polom K, Petrioli R, Marano L, Marrelli D, et al. Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. Cancer Lett 2016; 372:187-191.
10. Ding J, Chen X, Gao Z, Dai X, Li L, Xie C, et al. Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans. Drug Metab 2013; 41:1195-1210.
11. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 2009; 6:569-579.
12. Ding J, Chen X, Dai X, Zhong D. Simultaneous determination of apatinib and its four major metabolites in human plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study. J Chromatogr B 2012; 895-896:108-115.
13. Scott AJ, Messersmith WA, Jimeno A. Apatinib: a promising oral antiangiogenic agent in the treatment of multiple solid tumors. Drugs  Today 2015; 51:223-229.
14. Yang J, Carra S, Zhu WG, Kampinga HH. The regulation of the autophagic network and its implications for human disease. Int J Biol Sci 2013; 9:1121-1133.
15. Aoyama T, Yoshikawa T. Targeted therapy: Apatinib - new third-line option for refractory gastric or GEJ cancer. Nat Rev Clin Oncol 2016; 13:268-2670.
16. Roviello G, Ravelli A, Fiaschi AI, Cappelletti MR, Gobbi A, Senti C, et al. Apatinib for the treatment of gastric cancer. Exp Rev Gastroenterol Hepatol 2016; 10:887-892.
17. Tian S, Quan H, Xie C, Guo H, Lu F, Xu Y, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci 2011; 102:1374-1380.
18. Li J, Zhao X, Chen L, Guo H, Lv F, Jia K, et al. Safety and
pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer 2010; 10:529.
19. Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J  2016; 30:3961-3978.
20. Chan MM, Sjoquist KM, Zalcberg JR. Clinical utility of ramucirumab in advanced gastric cancer. Biologics  2015; 9:93-105.
21. Fornaro L, Vasile E, Falcone A. Apatinib in Advanced Gastric Cancer: A Doubtful Step Forward. J Clin Oncol 2016; pii: JCO686931.
22. Ahlberg J, Glaumann H. Uptake--microautophagy--and degradation of exogenous proteins by isolated rat liver lysosomes. Effects of pH, ATP, and inhibitors of proteolysis. Exp Mol Pathol 1985; 42:78-88.
23. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27-42.
24. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451:1069-1075.
25. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-484.
26. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13:132-141.
27. Lee JJ, Chu E. Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer. Clin Colorectal Cancer 2014; 13:135-144.