Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate.
Phospho-sulindac inhibits pancreatic cancer growth: NFATc1 as a drug resistance candidate.
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DOI：
10.3892/ijo.2013.2190
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发表时间：
2014-02
影响因子：
5.2
通讯作者：
Rigas B
中科院分区：
文献类型：
--
作者：
Murray OT;Wong CC;Vrankova K;Rigas B
Phospho-sulindac （P-S）是一种很有前景的抗癌药物，在人类癌症的临床前模型中是有效的，并且显然是安全的。我们研究了P-S对胰腺癌生长的影响。我们发现P-S在体外对人胰腺癌细胞的生长有强烈的抑制作用，对裸鼠胰腺异种移植物的生长有有效的抑制作用，并且具有良好的安全性。微阵列分析显示，P-S诱导活化t细胞核因子c1亚型（NFATc1）基因的表达。与侵袭性胰腺癌相关的钙调神经蛋白应答转录因子NFATc1。在体外和体内，通过沉默或过表达NFATc1来评估NFATc1表达增加对P-S对肿瘤生长的抑制作用。我们发现，当RNAi消除NFATc1的表达时，胰腺癌细胞对P-S治疗的反应更强。相反，过表达NFATc1基因使胰腺癌细胞对P-S治疗反应较差。NFATc1可能介导P-S耐药，是预测肿瘤不良反应的不利预后因素。我们还证明了nfatc1介导的耐药可以被环孢素A（一种NFAT抑制剂）克服，并且P-S和CsA的联合可以协同抑制胰腺癌细胞的生长。总之，我们的临床前数据表明P-S在临床前模型中是一种有效的胰腺癌药物，值得进一步评价。
Phospho-sulindac (P-S), a promising anticancer agent, is efficacious in pre-clinical models of human cancer and is apparently safe. Here, we studied the effect of P-S on pancreatic cancer growth. We found that P-S strongly inhibits the growth of human pancreatic cancer cells in vitro, is efficacious in inhibiting the growth of pancreatic xenografts in nude mice, and has an excellent safety profile. Microarray analysis revealed that P-S induced the expression of nuclear factor of activated T-cells, isoform c1 (NFATc1) gene. NFATc1, a calcineurin-responsive transcription factor associated with aggressive pancreatic cancer. The role of increased NFATc1 expression on the growth inhibitory effect of P-S on cancer growth was evaluated by silencing or by overexpressing it both in vitro and in vivo. We found that when the expression of NFATc1 was abrogated by RNAi, pancreatic cancer cells were more responsive to treatment with P-S. Conversely, over-expressing the NFATc1 gene made the pancreatic cancer cells less responsive to treatment with P-S. NFATc1 likely mediates drug resistance to P-S and is an unfavorable prognostic factor that predicts poor tumor response. We also demonstrated that NFATc1-mediated resistance can be overcome by cyclosporin A (CsA), an NFAT inhibitor, and that the combination of P-S and CsA synergistically inhibited pancreatic cancer cell growth. In conclusion, our preclinical data establish P-S as an efficacious drug for pancreatic cancer in preclinical models, which merits further evaluation.
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影响因子：
11.2
作者：
Sun Y;Rigas B
通讯作者：
Rigas B
影响因子：
50.3
作者：
Gregory MA;Phang TL;Neviani P;Alvarez-Calderon F;Eide CA;O'Hare T;Zaberezhnyy V;Williams RT;Druker BJ;Perrotti D;Degregori J
通讯作者：
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DOI：
10.1006/bbrc.2002.6614
发表时间：
2002-03-22
影响因子：
3.1
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通讯作者：
Li, YB
影响因子：
5.7
作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
Rigas, Basil