title: Synergistic inhibition of sunitinib and ethaselen against human colorectal cancer cells proliferation.
abstract: Sunitinib, a multi-targeted tyrosine kinase inhibitor, has been widely used in the therapy of advanced renal cell cancer and imatinib-resistant gastrointestinal stromal tumors. However, little benefits could be obtained from sunitinib for patients with other types of solid tumors including colorectal cancer (CRC). Ethaselen (BBSKE), a specific thioredoxin reductase 1 inhibitor, has shown convincing anticancer effects both in vivo and in vitro. In this study, we explored the combinatory effect of sunitinib and BBSKE in human CRC cell lines LoVo, HT-29 and RKO. Cotreatment of BBSKE and sunitinib with the ratio of 2:1 for 24h displayed synergistic effect against CRC cells proliferation. Apoptosis analysis also revealed that combination treatment of BBSKE and sunitinib (2:1) for 24h induced higher apoptosis rate than either single treatment. The synergistic effect against LoVo cells proliferation may be explained by sharp reduction of Bcl-2/Bax protein expression ratio, decrease of pro-Caspase-3 protein expression along with significantly augmented Caspase-3 enzymatic activity, and release of cytochrome C from mitochondria to cytoplasm in the combination treatment group. The significant inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation might also account for the synergism in cotreatment group. In short, sunitinib plus BBSKE is perhaps a promising strategy for colorectal cancer therapy.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Yunhan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
authors.forename: Ruoxuan
authors.initials: R
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China. Electronic address: zenghh@bjmu.edu.cn.
authors.forename: Huihui
authors.initials: H
authors.lastname: Zeng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C478160:(1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone))ethane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D016566:Organoselenium Compounds; D011758:Pyrroles; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib
keywords: Bcl-2/Bax; Colorectal cancer; Cytochrome C; Ethaselen; Sunitinib; VEGFR