A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer
A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer
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一种新型BMI-1抑制剂QW24用于治疗干细胞样结直肠癌
DOI：
10.1186/s13046-019-1392-8
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发表时间：
2019-10
影响因子：
11.3
通讯作者：
Liu Mingyao
中科院分区：
文献类型：
--
作者：
Wang Jinhua;Xing Yajing;Wang Yingying;He Yundong;Wang Liting;Peng Shihong;Yang Lianfang;Xie Jiuqing;Li Xiaotao;Qiu Wenwei;Yi Zhengfang;Liu Mingyao
BackgroundCancer-initiating cell (CIC), a functionally homogeneous stem-like cell population, is resonsible for driving the tumor maintenance and metastasis, and is a source of chemotherapy and radiation-therapy resistance within tumors. Targeting CICs self-renewal has been proposed as a therapeutic goal and an effective approach to control tumor growth. BMI-1, a critical regulator of self-renewal in the maintenance of CICs, is identified as a potential target for colorectal cancer therapy.MethodsColorectal cancer stem-like cell lines HCT116 and HT29 were used for screening more than 500 synthetic compounds by sulforhodamine B (SRB) cell proliferation assay. The candidate compound was studied in vitro by SRB cell proliferation assay, western blotting, cell colony formation assay, quantitative real-time PCR, flow cytometry analysis, and transwell migration assay. Sphere formation assay and limiting dilution analysis (LDA) were performed for measuring the effect of compound on stemness properties. In vivo subcutaneous tumor growth xenograft model and liver metastasis model were performed to test the efficacy of the compound treatment. Student’s t test was applied for statistical analysis.ResultsWe report the development and characterization of a small molecule inhibitor QW24 against BMI-1. QW24 potently down-regulates BMI-1 protein level through autophagy-lysosome degradation pathway without affecting the BMI-1 mRNA level. Moreover, QW24 significantly inhibits the self-renewal of colorectal CICs in stem-like colorectal cancer cell lines, resulting in the abrogation of their proliferation and metastasis. Notably, QW24 significantly suppresses the colorectal tumor growth without obvious toxicity in the subcutaneous xenograft model, as well as decreases the tumor metastasis and increases mice survival in the liver metastasis model. Moreover, QW24 exerts a better efficiency than the previously reported BMI-1 inhibitor PTC-209.ConclusionsOur preclinical data show that QW24 exerts potent anti-tumor activity by down-regulating BMI-1 and abrogating colorectal CICs self-renewal without obvious toxicity in vivo, suggesting that QW24 could potentially be used as an effective therapeutic agent for clinical colorectal cancer treatment.
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DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
雄激素受体剪接变体与组成性开放染色质结合并促进前列腺癌的阿比特龙耐药生长
影响因子：
14.9
作者：
He Y;Lu J;Ye Z;Hao S;Wang L;Kohli M;Tindall DJ;Li B;Zhu R;Wang L;Huang H
通讯作者：
Huang H
上皮-间质转化与球体来源的干样结肠癌细胞干性的维持相关。
影响因子：
3.7
作者：
Han XY;Wei B;Fang JF;Zhang S;Zhang FC;Zhang HB;Lan TY;Lu HQ;Wei HB
通讯作者：
Wei HB
影响因子：
37.3
作者：
Botchkina GI;Zuniga ES;Das M;Wang Y;Wang H;Zhu S;Savitt AG;Rowehl RA;Leyfman Y;Ju J;Shroyer K;Ojima I
通讯作者：
Ojima I
影响因子：
5.2
作者：
Teo WH;Chen HP;Huang JC;Chan YJ
通讯作者：
Chan YJ