Synergistic inhibition of sunitinib and ethaselen against human colorectal cancer cells proliferation

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• 作者：Xiaoqing Zheng^a ; ^b ; Yunhan Zhang^a ; ^b ; Lei Zhang^a ; ^b ; Wei Xu^a ; ^b ; Weiwei Ma^a ; ^b ; Ruoxuan Sun^a ; ^b ; Huihui Zeng^a ; ^b ; ^{zenghh@bjmu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：TKI ; tyrosine kinase inhibitor ; VEGFRs ; vascular endothelial growth factor receptors ; PDGFRs ; platelet-derived growth factor receptors ; NSCLC ; non-small cell lung cancer ; Trx ; thioredoxin ; TrxR ; thioredoxin reductase ; BBSKE ; ethaselen ; ROS ; reactive oxygen species ; CRC ; colorectal cancer ; SRB ; sulforhodamine B ; CI ; combination index ; DRI ; dose-reduction index ; MI ; maximum inhibition rate
• 刊名：Biomedicine & Pharmacotherapy
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：83
• 期：Complete
• 页码：212-220
• 全文大小：1407 K

文摘

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 24 h displayed synergistic effect against CRC cells proliferation. Apoptosis analysis also revealed that combination treatment of BBSKE and sunitinib (2:1) for 24 h 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.