Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts (Retracted article. See vol. 122, pg. 3247, 2016)
Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts (Retracted article. See vol. 122, pg. 3247, 2016)
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DOI：
10.1002/cncr.21731
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发表时间：
2006-03-15
期刊：
影响因子：
6.2
通讯作者：
Sarkar, FH
中科院分区：
文献类型：
--
作者：
Mohammad, RM;Banerjee, S;Sarkar, FH
背景资料。核因子-kappaB的激活参与了胰腺癌的耐药过程。作者先前发现，大豆异黄酮染料木素在体外下调了许多癌细胞系中核因子-kappaB的激活。在本研究中，他们的研究重点是检测金雀异黄素对核因子-kappaB的失活在体外是否能增强顺铂对BxPC-3细胞的生长抑制和凋亡作用，以及顺铂在体内的抗肿瘤活性。细胞生长抑制实验、细胞凋亡实验和核因子-kappa B凝胶迁移率改变实验。对于体内研究，使用了BxPC-3细胞在严重联合免疫缺陷小鼠的异种移植模型。金雀异黄素800 mU/kg灌胃给药5天，顺铂9 mg/kg腹腔注射，另一组小鼠同时给予顺铂和金雀异黄素4天。结果：25 mU金雀异黄素与0.5 mU顺铂合用对BxPC-3细胞的生长抑制作用明显增强(P<0.01)，细胞凋亡率显著增加(P<0.01)。金雀异黄素可阻断顺铂诱导的核因子-kappaB的活化，这似乎与作者的假设一致。作者还首次证明了金雀异黄素的体内效应增强了顺铂的抗肿瘤活性。对照组、金雀异黄素、顺铂和金雀异黄素与顺铂联合用药小鼠的肿瘤重量分别为940 mg、762 mg、261 mg和108 mg。最重要的是，作者首次观察到，在金雀异黄素处理的动物肿瘤中，核因子-kappa B的DNA结合活性被灭活，而顺铂显著地诱导了核因子-kappaB的DNA结合活性，而在暴露于顺铂的肿瘤中，这种结合活性被完全取消，这与体外数据一致。结论总体上，目前的结果与作者的假设一致，表明金雀异黄素预处理胰腺癌细胞下调核因子-kappa B的活性，有助于增强顺铂的诱导凋亡作用，从而在体内产生更强的抗肿瘤活性。
BACKGROUND. The activation of nuclear factor kappa B (NF-kappa B) contributes to drug resistance in pancreatic carcinoma. The authors previously showed that the soy isoflavone genistein down-regulates the activation of NF-kappa B in many carcinoma cell lines in vitro. In the current study, they focused their investigation on testing whether the inactivation of NF-kappa B by genistein could enhance cisplatin-induced cell growth inhibition and apoptosis in BxPC-3 cells in vitro and antitumor activity of cisplatin in vivo.METHODS. BxPC-3 cells were preexposed to 25 mu M genistein for 24 hours and then exposed to cisplatin (0.5 mu M) for an additional 72 hours. A cell growth inhibition assay, an apoptosis assay, and an NF-kappa B electrophoretic mobility shift assay were conducted. For the in vivo study, a xenograft model of BxPC-3 cells in severe combined immunodeficient mice was used. Genistein was given at a dose of 800 mu g/kg orally for 5 days, cisplatin was given at a dose of 9 mg/kg as an intraperitoneal bolus, and another group of mice received both cisplatin and genistein (given on Day 1 concurrently followed by genistein for 4 days).RESULTS. The combination of 25 mu M genistein with 0.5 mu M cisplatin resulted in significantly greater growth inhibition (P < 0.01) and more apoptosis in BxPC-3 cells compared with either agent alone. Preexposure of BYPC-3 cells to genistein abrogated cisplatin-induced activation of NF-kappa B, which appeared to be consistent with the authors' hypothesis. The authors also demonstrated for the first time that the in vivo effect of genistein enhanced the antitumor activity of cisplatin. The tumor weight for the control, genistein, cisplatin, and combined genistein and cisplatin mice was 940 mg, 762 mg, 261 mg, and 108 mg, respectively. Most important, for the first time, the authors observed that the DNA-binding activity of NF-kappa B was inactivated in genistein-treated animal tumors, whereas cisplatin significantly induced NF-kappa B DNA binding activity, and this was completely abrogated in genistein-pretreated tumors that were exposed to cisplatin, consistent with the in vitro data.CONCLUSIONS. overall, the current results were consistent with the authors' hypothesis and suggested that pretreatment of pancreatic carcinoma cells with genistein down-regulates NF-kappa B activity and contributes toward enhancing the apoptosis-inducing effect of cisplatin, leading to greater antitumor activity in vivo.