Famitinib exerted powerful antitumor activity in human gastric cancer cells and xenografts

Ge,Sai; Zhang,Qiyue; He,Qiong; Zou,Jianling; Liu,Xijuan; Li,Na; Tian,Tiantian; Zhu,Yan; Gao,Jing; Shen,Lin

doi:10.3892/ol.2016.4909

Famitinib exerted powerful antitumor activity in human gastric cancer cells and xenografts

Authors:
- Sai Ge
- Qiyue Zhang
- Qiong He
- Jianling Zou
- Xijuan Liu
- Na Li
- Tiantian Tian
- Yan Zhu
- Jing Gao
- Lin Shen
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Affiliations: Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
Published online on: July 25, 2016 https://doi.org/10.3892/ol.2016.4909
Pages: 1763-1768
Copyright: © Ge et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Famitinib (SHR1020), a novel multi-targeted tyrosine kinase inhibitor, has antitumor activity against several solid tumors via targeting vascular endothelial growth factor receptor 2, c‑Kit and platelet‑derived growth factor receptor β. The present study investigated famitinib's activity against human gastric cancer cells in vitro and in vivo. Cell viability and apoptosis were measured, and cell cycle analysis was performed following famitinib treatment using 3-(4,5-dimethylthiazol -2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling assay and western blotting. Subsequently, cluster of differentiation 34 staining was used to evaluate microvessel density. BGC-823-derived xenografts in nude mice were established to assess drug efficacy in vivo. Famitinib inhibited cell proliferation by inducing cell cycle arrest at the G2/M phase and caused cell apoptosis in a dose‑dependent manner in gastric cancer cell lines. In BGC‑823 xenograft models, famitinib significantly slowed tumor growth in vivo via inhibition of angiogenesis. Compared with other chemotherapeutics such as 5-fluorouracil, cisplatin or paclitaxel alone, famitinib exhibited the greatest tumor suppression effect (>85% inhibition). The present study demonstrated for the first time that famitinib has efficacy against human gastric cancer in vitro and in vivo, which may lay the foundations for future clinical trials.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ajani JA, Bentrem DJ, Besh S, D'Amico TA, Das P, Denlinger C, Fakih MG, Fuchs CS, Gerdes H, Glasgow RE, et al: National Comprehensive Cancer Network: Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 11:531–546. 2013.PubMed/NCBI
3	Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, et al: Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol. 14:e535–e547. 2013. View Article : Google Scholar : PubMed/NCBI
4	Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 376:687–697. 2010. View Article : Google Scholar : PubMed/NCBI
5	Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J and Lydon NB: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 2:561–566. 1996. View Article : Google Scholar : PubMed/NCBI
6	Barker AJ, Gibson KH, Grundy W, Godfrey AA, Barlow JJ, Healy MP, Woodburn JR, Ashton SE, Curry BJ, Scarlett L, et al: Studies leading to the identification of ZD1839 (IRESSA): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett. 11:1911–1914. 2001. View Article : Google Scholar : PubMed/NCBI
7	Perez-Soler R: The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res. 10:4238s–4240s. 2004. View Article : Google Scholar : PubMed/NCBI
8	Rask-Andersen M, Zhang J, Fabbro D and Schiöth HB: Advances in kinase targeting: Current clinical use and clinical trials. Trends Pharmacol Sci. 35:604–620. 2014. View Article : Google Scholar : PubMed/NCBI
9	Yang W, Raufi A and Klempner SJ: Targeted therapy for gastric cancer: Molecular pathways and ongoing investigations. Biochim Biophys Acta. 1846:232–237. 2014.PubMed/NCBI
10	Lou L, Mi Y, Xu Y, Xie C and Zhao H: Preclinical antitumor study of famitinib, an orally available multi-targeted kinase inhibitor of VEGFR/PDGFR/c-Kit in phase I clinical trials. Proceedings of AACR 102nd Annual Meeting (Cancer Res, Orlando, FL). 712011.
11	Zhou A, Zhang W, Chang C, Chen X, Zhong D, Qin Q, Lou D, Jiang H and Wang J: Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Cancer Chemother Pharmacol. 72:1043–1053. 2013. View Article : Google Scholar : PubMed/NCBI
12	Zhang W, Zhou AP, Qin Q, Chang CX, Jiang HY, Ma JH and Wang JW: Famitinib in metastatic renal cell carcinoma: A single center study. Chin Med J (Engl). 126:4277–4281. 2013.PubMed/NCBI
13	Xie C, Zhou J, Guo Z, Diao X, Gao Z, Zhong D, Jiang H, Zhang L and Chen X: Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 168:1687–1706. 2013. View Article : Google Scholar : PubMed/NCBI
14	Cao J, Zhang J, Wang Z, Wang B, Lv F, Wang L and Hu X: Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR-2 inhibitor in metastatic breast cancer. Cancer Chemother Pharmacol. 74:389–398. 2014. View Article : Google Scholar : PubMed/NCBI
15	He Q, Gao J, Ge S, Wang T, Li Y, Peng Z, Li Y and Shen L: 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. View Article : Google Scholar : PubMed/NCBI
16	Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, et al: Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol. 14:e535–e547. 2013. View Article : Google Scholar : PubMed/NCBI
17	Folkman J: Tumor angiogenesis: Therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
18	Shen L, Li J, Xu J, Pan H, Dai G, Qin S, Wang L, Wang J, Yang Z, Shu Y, et al: Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: Randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 18:168–176. 2015. View Article : Google Scholar : PubMed/NCBI
19	Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 29:3968–3976. 2011. View Article : Google Scholar : PubMed/NCBI
20	Martin-Richard M, Gallego R, Pericay C, Foncillas Garcia J, Queralt B, Casado E, Barriuso J, Iranzo V, Juez I, Visa L, et al: Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study. Invest New Drugs. 31:1573–1579. 2013. View Article : Google Scholar : PubMed/NCBI
21	Ilson DH: Angiogenesis in gastric cancer: Hitting the target? Lancet. 383:4–6. 2014. View Article : Google Scholar : PubMed/NCBI
22	Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, dos Santos LV, Aprile G, Ferry DR, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase III trial. Lancet. 383:31–39. 2014. View Article : Google Scholar : PubMed/NCBI
23	Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, et al: Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: Results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol. 31:3219–3225. 2013. View Article : Google Scholar : PubMed/NCBI