Abstract
Objective
As the new oral selective VEGFR tyrosine kinase inhibitor, axitinib (AG-013736) exerts powerful antitumor activity in multiple solid tumors, while its’ effect was unclear in gastric cancer. We aimed to investigate the antitumor activity of axitinib alone or combined with chemotherapeutic drugs against human gastric cancer cells in vitro and in vivo.
Methods
The IC50 values of drugs were determined by MTS assay. The median effect of Chou-Talalay was used to assess the synergistic effect of two drugs. Flow cytometry was employed to analyze cell cycle and cell apoptosis. Cell senescence and microvessel density were evaluated by SA-β-gal staining and CD34 staining, respectively. BGC-823-derived xenografts in nude mice were established to investigate the effects of drugs in vivo.
Results
Axitinib alone could inhibit cell proliferation and retard tumor growth through inducing cell cycle arrest at G2/M phase, cell senescence, cell apoptosis, and antiangiogenesis in vitro and in vivo. Axitinib combined with 5-fluorouracil (5-FU) had synergistic inhibitory effect compared to axitinib or 5-FU alone. However, the highest inhibitory effect was found between axitinib and cisplatin (inhibitory ratio >80 % compared to control), which was significantly higher than any single drug (inhibitory ratio for single 5-FU, cisplatin, and axitinib >10, >40, and >40 %, respectively, compared to control) or axitinib combined with 5-FU (inhibitory ratio >50 % compared to control).
Conclusion
We highlighted for the first time that axitinib alone or in combination with 5-fluorouracil or cisplatin has potent antitumor activity against human gastric cancer in vitro and in vivo, which provided solid evidence for future clinical trial.
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References
Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V et al (2010) Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 28(9):1547–1553
Canu B, Fioravanti A, Orlandi P, Di Desidero T, Alì G, Fontanini G et al (2011) Irinotecan synergistically enhances the antiproliferative and proapoptotic effects of axitinib in vitro and improves its anticancer activity in vivo. Neoplasia 13(3):217–229
Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP et al (2008) Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26(29):4708–4713
Fruehauf J, Fruehauf J, Lutzky J, McDermott D, Brown CK, Meric JB et al (2011) Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res 17(23):7462–7469
Gao J, Lu M, Yu JW, Li YY, Shen L (2011) Thymidine phosphorylase/β-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. BMC Cancer 11:177–184
Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K et al (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14(22):7272–7283
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90
Kindler HL, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T et al (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomized phase 3 study. Lancet Oncol 12(3):256–262
Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M et al (2008) S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 9(3):215–221
Kozloff MF, Martin LP, Krzakowski M, Samuel TA, Rado TA, Arriola E et al (2012) Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours. Br J Cancer 107(8):1277–1285
Li KL, Wilmes LJ, Henry RG, Pallavicini MG, Park JW, Hu-Lowe DD et al (2005) Heterogeneity in the angiogenic response of a BT474 human breast cancer to a novel vascular endothelial growth factor-receptor tyrosine kinase inhibitor: assessment by voxel analysis of dynamic contrast-enhanced MRI. J Magn Reson Imaging 22(4):511–519
Liu G, Rugo HS, Wilding G, McShane TM, Evelhoch JL, Ng C et al (2005) Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol 23(24):5464–5473
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet 378(9807):1931–1939
Rössler J, Monnet Y, Farace F, Opolon P, Daudigeos-Dubus E, Bourredjem A et al (2011) The selective VEGFR1-3 inhibitor (AG-013736) shows antitumor activity in human neuroblastoma xenografts. Int J Cancer 128(11):2748–2758
Rugo HS, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A et al (2011) Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol 29(18):2459–2465
Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E et al (2009) Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study. J Clin Oncol 27(23):3836–3841
Sharma S, Abhyankar V, Burgess RE, Infante J, Trowbridge RC, Tarazi J et al (2010) A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol 21(2):297–304
Stehle F, Schulz K, Fahldieck C, Kalich J, Lichtenfels R, Riemann D et al (2013) Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors. J Biol Chem 288(23):16334–16347
Ulahannan SV, Brahmer JR (2011) Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer. Cancer Invest 29(4):325–337
Wang T, Gao J, Yu J, Shen L (2013) Synergistic inhibitory effect of wogonin and low-dose paclitaxel on gastric cancer cells and tumor xenografts. Chin J Cancer Res 25(5):505–513
Yu J, Gao J, Lu Z, Li Y, Shen L (2012) Serum levels of TUBB3 correlate with clinical outcome in Chinese patients with advanced gastric cancer receiving first-line paclitaxel plus capecitabine. Med Oncol 29(5):3029–3034
Acknowledgments
This work was supported by National Natural Science Foundation of China (No. 81172110), National High Technology Research and Development Program (No. 2012AA 02A 504), and Beijing Municipal Science and Technology Commission Program (No. Z11110706730000). The authors thank Pfizer for the providing of axitinib and Dr. Zhongwu Li (Department of pathology, Peking University Cancer Hospital and Institute) for the IHC scoring.
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The authors declare that they have no conflict of interest.
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Qiong He, Jing Gao, and Sai Ge have contributed equally to this work.
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He, Q., Gao, J., Ge, S. et al. Axitinib alone or in combination with chemotherapeutic drugs exerts potent antitumor activity against human gastric cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 140, 1575–1583 (2014). https://doi.org/10.1007/s00432-014-1693-4
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DOI: https://doi.org/10.1007/s00432-014-1693-4