Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling.
Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling.
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eflornithine（DFMO）通过调节鸟氨酸脱羧酶信号传导来防止胰腺癌的进展。
DOI：
10.1158/1940-6207.capr-14-0176
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Rao CV
中科院分区：
文献类型：
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作者：
Mohammed A;Janakiram NB;Madka V;Ritchie RL;Brewer M;Biddick L;Patlolla JM;Sadeghi M;Lightfoot S;Steele VE;Rao CV
鸟氨酸脱羧酶（ODC）是多胺合成途径中的关键限速酶，在多种癌症中过表达。我们发现多胺合成和ODC信号的调节发生在胰腺前体病变的早期阶段，并且随着Kras激活的p48 Cre/+-LSL-KrasG 12 D/+小鼠中肿瘤的进展而增加。近年来，由于ODC被c-myc癌基因反式激活，并与ras癌基因在上皮组织的恶性转化中协同作用，因此ODC抑制剂依氟鸟氨酸（DFMO）作为癌症化学预防剂的应用越来越受到关注。我们测试了DFMO对胰腺上皮内肿瘤（PanIN）及其在基因工程Kras小鼠中进展为胰腺导管腺癌（PDAC）的影响。与喂食对照饮食的小鼠相比，喂食饮食中0.1和0.2% DFMO的KrasG 12 D/+小鼠显示出对PDAC发生率的显著抑制（p<0.0001）。两种剂量的DFMO均使胰腺肿瘤重量降低31-43%（p<0.03-0.001）。0.1和0.2%的DFMO对PanIN 3病变（原位癌）产生显著抑制（27和31%，P<0.02-0.004）。DFMO处理的胰腺表现出调制的ODC通路组件沿着与减少的增殖和增加的p21/p27的表达相比，胰腺组织来源于喂食对照饮食。总之，我们的临床前数据表明，DFMO具有化学预防胰腺癌的潜力，应在其他PDAC模型中进行评估，并与其他药物联合进行未来的临床试验。
Ornithine decarboxylase (ODC) is the key rate limiting enzyme in the polyamine synthesis pathway and it is overexpressed in a variety of cancers. We found that polyamine synthesis and modulation of ODC signaling occurs at early stages of pancreatic precursor lesions and increases as the tumor progresses in Kras activated p48Cre/+-LSL-KrasG12D/+ mice. Interest in use of the ODC inhibitor Eflornithine (DFMO) as a cancer chemopreventive agent has increased in recent years since ODC was shown to be transactivated by the c-myc oncogene and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. We tested the effects of DFMO on pancreatic intraepithelial neoplasms (PanINs) and their progression to pancreatic ductal adenocarcinoma (PDAC) in genetically engineered Kras mice. The KrasG12D/+ mice fed DFMO at 0.1 and 0.2 % in the diet showed a significant inhibition (p<0.0001) of PDAC incidence compared with mice fed control diet. Pancreatic tumor weights were decreased by 31–43% (p<0.03–0.001) with both doses of DFMO. DFMO at 0.1 and 0.2 % caused a significant suppression (27 and 31%, P<0.02–0.004) of PanIN 3 lesions (carcinoma in situ). DFMO-treated pancreas exhibited modulated ODC pathway components along with decreased proliferation and increased expression of p21/p27 as compared with pancreatic tissues derived from mice fed control diet. In summary, our preclinical data indicate that DFMO has potential for chemoprevention of pancreatic cancer and should be evaluated in other PDAC models and in combination with other drugs in anticipation of future clinical trials.