自噬
体内
氯喹
细胞凋亡
联合疗法
结直肠癌
药理学
氟尿嘧啶
癌症
癌症研究
医学
生物
免疫学
内科学
生物化学
生物技术
疟疾
作者
Kazuhito Sasaki,Nelson H. Tsuno,Eiji Sunami,Kazushige Kawai,Kumiko Hongo,Masaya Hiyoshi,Manabu Kaneko,Koji Murono,Noriko Tada,Takako Nirei,Koki Takahashi,Joji Kitayama
出处
期刊:Anti-Cancer Drugs
[Ovid Technologies (Wolters Kluwer)]
日期:2012-05-03
卷期号:23 (7): 675-682
被引量:63
标识
DOI:10.1097/cad.0b013e328353f8c7
摘要
Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer.
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