Cancer Cell：杀死癌细胞新联合疗法

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Cancer Cell：杀死癌细胞新联合疗法 生物通报道：美国宾州大学医学院的研究救人员确定出一种敏化抗性人类癌细胞以使其对正在临床检测的一种药物起反应的新联合疗法。他们表示，这种疗法可能有助于有选择地消除癌细胞而不伤害健康细胞，从而降低癌症治疗的副作用。这项研究的结果发表在7月的CancerCell杂志上。为了检测这种联合疗法对付癌变肿瘤的能力，WafikS.El-Deiry博士和同事用一种肿瘤坏死因子TRAIL和一种目前用于治疗肾癌的抑制剂——sorafenib治疗患有结肠癌的小鼠。测试结果显示，这种sorafenib和TRAIL药物能够缩小小鼠体内的肿瘤并且副作用很小，从而证实这种联合药物疗法对人类结肠癌的治疗潜力。TRAIL即TN

  生物谷报道：美国宾州大学医学院的研究救人员确定出一种敏化抗性人类癌细胞以使其对正在临床检测的一种药物起反应的新联合疗法。他们表示，这种疗法可能有助于有选择地消除癌细胞而不伤害健康细胞，从而降低癌症治疗的副作用。这项研究的结果发表在7月的Cancer Cell杂志上。

  为了检测这种联合疗法对付癌变肿瘤的能力，Wafik S. El-Deiry博士和同事用一种肿瘤坏死因子TRAIL和一种目前用于治疗肾癌的抑制剂——sorafenib治疗患有结肠癌的小鼠。

  测试结果显示，这种sorafenib和TRAIL药物能够缩小小鼠体内的肿瘤并且副作用很小，从而证实这种联合药物疗法对人类结肠癌的治疗潜力。

  TRAIL即TNF-a-related凋亡诱导配基，是一种由身体免疫细胞产生并促进细胞死亡的天然分子）在目前正在进行的临床试验中，医生施还让癌症患者使用TRAIL来帮助杀死癌细胞。

  尽管以TRAIL为基础的疗法很有潜力，但是超过50％的癌细胞还是对TRAIL表现出了抗性。为了创造出一种更强大的靶向癌症疗法，该研究组开始寻找能够逆转癌细胞对TRAIL抗性的途径。

  就是在近期，该研究组发现TRAIL康熙细胞能够通过产生一种叫做cIAP2和Mcl-2的存活蛋白来逃过死亡的命运。癌基因c-Myc在一定程度上通过抑制一种中间蛋白（一种监控cIAP2和Mcl-1蛋白的蛋白质）的功能来阻止癌细胞存活。没有这些存活蛋白，癌细胞就不能对由TRAIL启动的死亡程序产生抗性。

  在寻找与c-Myc具有相似功能的药物时，研究组对sorafenib进行了研究。他们发现，这种药物在与TRAIL结合使用时，与c-Myc一样，都能抑制中间体和存活蛋白，从而导致抗TRAIL的结肠和肺癌细胞系死亡。

原始出处:

Cancer Cell, Vol 12, 66-80, 10 July 2007
Article

Reduction of TRAIL-Induced Mcl-1 and cIAP2 by c-Myc or Sorafenib Sensitizes Resistant Human Cancer Cells to TRAIL-Induced Death

M. Stacey Ricci,1,2,3,4,5,6,9,12 Seok-Hyun Kim,1,2,3,4,5,6,12 Kazuhiro Ogi,1,2,3,4,5,6 John P. Plastaras,1,2,3,4,5,6 Jianhua Ling,8 Wenge Wang,1,2,3,4,5,6 Zhaoyu Jin,1,2,3,4,5,6,10 Yingqiu Y. Liu,1,2,3,4,5,6 David T. Dicker,1,2,3,4,5,6 Paul J. Chiao,8 Keith T. Flaherty,2 Charles D. Smith,7,11 and Wafik S. El-Deiry1,2,3,4,5,6,

1 Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
2 Department of Medicine (Hematology/Oncology), University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
3 Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
4 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
5 The Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
6 The Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
7 Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA
8 Departments of Surgical Oncology and Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA


Corresponding author
Wafik S. El-Deiry
wafik@mail.med.upenn.edu

Cells expressing oncogenic c-Myc are sensitized to TNF superfamily proteins. c-Myc also is an important factor in determining whether a cell is sensitive to TRAIL-induced apoptosis, and it is well established that the mitochondrial pathway is essential for apoptosis induced by c-Myc. We investigated whether c-Myc action on the mitochondria is required for TRAIL sensitivity and found that Myc sensitized cells with defective intrinsic signaling to TRAIL. TRAIL induced expression of antiapoptotic Mcl-1 and cIAP2 through activation of NF-κB. Both Myc and the multikinase inhibitor sorafenib block NF-κB. Combining sorafenib with TRAIL in vivo showed dramatic efficacy in TRAIL-resistant tumor xenografts. We propose the combination of TRAIL with sorafenib holds promise for further development.