Antitumor activity of a novel oncrasin analogue is mediated by JNK activation and STAT3 inhibition.
Antitumor activity of a novel oncrasin analogue is mediated by JNK activation and STAT3 inhibition.
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DOI：
10.1371/journal.pone.0028487
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Guo W;Wu S;Wang L;Wei X;Liu X;Wang J;Lu Z;Hollingshead M;Fang B
为了优化oncrasin-1的抗肿瘤活性，通过对同基因K-Ras突变肿瘤细胞的合成致死性筛选鉴定的小分子，我们开发了几种类似物并测定了它们的抗肿瘤活性。在这里，我们研究了NSC-743380（1-[（3-氯苯基）甲基]-1H-吲哚-3-甲醇，oncrasin-72）的体外和体内抗肿瘤活性，oncrasin-1的最有效的类似物之一。 使用细胞活力测定法在NCI-60癌细胞系组中测定体外抗肿瘤活性。与NSC-741909（oncrasin-60）在裸鼠中建立的A498（一种人肾癌细胞系）异种移植瘤中平行测定体内抗肿瘤活性。通过蛋白质印迹分析，在乳腺癌和肾癌细胞中分析了用NSC-743380处理后基因表达水平和信号传导途径活性的变化。Western blot和流式细胞仪检测细胞凋亡。NSC-743380对源自人肺癌、结肠癌、卵巢癌、肾癌和乳腺癌的癌细胞系亚群具有高度活性。8种最敏感细胞系的50%生长抑制浓度（GI 50）≤10 nM。体内研究表明，NSC-743380具有比NSC-741909更好的安全性特征和更大的抗肿瘤活性。在67 mg/kg至150 mg/kg的试验剂量范围内，NSC-743380治疗导致裸鼠中A498异种移植肿瘤完全消退。机制表征显示，NSC-743380抑制RNA聚合酶II的C-末端结构域的磷酸化，诱导JNK活化，抑制JAK 2/STAT 3磷酸化，并抑制敏感的人癌细胞中的细胞周期蛋白D1表达。阻断JNK活化或组成型活性STAT 3的过表达部分阻断了NSC-743380诱导的抗肿瘤活性。NSC-743380通过调节多种癌症相关途径的功能诱导抗肿瘤活性，可能成为某些实体瘤的潜在抗癌药物。
To optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1. In vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI50) for eight of the most sensitive cell lines was ≤10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity. NSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
11.4
作者：
Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
通讯作者：
Johnson, Louise N.
影响因子：
4.8
作者：
Lim, CP;Cao, XM
通讯作者：
Cao, XM
全基因组的RNAi筛查鉴定了与RAS癌基因的多种合成致死相互作用。
影响因子：
64.5
作者：
Luo J;Emanuele MJ;Li D;Creighton CJ;Schlabach MR;Westbrook TF;Wong KK;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE