Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer.
Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer.
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DOI：
10.1371/journal.pone.0017850
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发表时间：
2011-03-09
期刊：
影响因子：
3.7
通讯作者：
Sarkar FH
中科院分区：
文献类型：
--
作者：
Bao B;Ali S;Kong D;Sarkar SH;Wang Z;Banerjee S;Aboukameel A;Padhye S;Philip PA;Sarkar FH
肿瘤组织中存在的肿瘤干细胞（cancer stem cells，CSCs）或肿瘤干细胞样细胞（cancer stem-like cells，CSCs）由于其内在和外在的耐药特性而被认为是肿瘤复发的原因。因此，靶向杀死肿瘤干细胞将是一种通过克服耐药性来预防肿瘤复发和/或治疗的新策略。我们开发了一种新的合成化合物-CDF，其在动物组织如胰腺中显示出更高的生物利用度，并且还诱导胰腺癌（PC）细胞中的细胞生长抑制和凋亡，这是通过NF-κ B、考克斯-2和VEGF的失活介导的。在当前的研究中，我们首次表明，CDF可以显著抑制PC细胞的球体形成能力（胰腺球），这与胰腺球崩解增加一致，这与CSC标志物（CD44和EpCAM）的衰减相关，特别是在含有高比例CSC的吉西他滨耐药（MIAPaCa-2）PC细胞中，这与miR-21增加和miR-200减少一致。在人PC异种移植小鼠模型中，CDF处理显著抑制肿瘤生长，这与肿瘤残留物中NF-κ B DNA结合活性、考克斯-2和miR-21表达降低以及PTEN和miR-200表达增加相关。这些结果强烈表明CDF的抗肿瘤活性与通过下调CSC相关信号传导途径抑制CSC功能相关。因此，CDF可用于预防肿瘤复发和/或治疗PC，在未来具有更好的治疗效果。
The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC) cells. In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants. These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
5.2
作者：
Kong, Dejuan;Li, Yiwei;Wang, Zhiwei;Banerjee, Sanjeev;Ahmad, Aamir;Kim, Hyeong-Reh Choi;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
影响因子：
2.5
作者：
Creighton, Chad J.;Chang, Jenny C.;Rosen, Jeffrey M.
通讯作者：
Rosen, Jeffrey M.
DOI：
10.2741/e117
发表时间：
2010-01-01
期刊：
Frontiers in bioscience (Elite edition)
影响因子：
--
作者：
Mueller, Maria-Theresa;Hermann, Patrick C;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
天然药物对 microRNA 的调节：化学预防和化疗研究的新兴领域。
影响因子：
3.7
作者：
Li, Yiwei;Kong, Dejuan;Wang, Zhiwei;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.