Cancer, 2006, 106(6):1260-1268.

Cisplatin-Induced Antitumor Activity Is Potentiated by the Soy Isoflavone Genistein in BxPC-3 Pancreatic Tumor Xenografts

Ramzi M. Mohammad, Sanjeev Banerjee, Yiwei Li, et al

Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA

BACKGROUND:

The activation of nuclear factor kappaB (NF-kappaB) contributes to drug resistance in pancreatic carcinoma. The authors previously showed that the soy isoflavone genistein down-regulates the activation of NF-kappaB in many carcinoma cell lines in vitro. In the current study, they focused their investigation on testing whether the inactivation of NF-kappaB 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 microM genistein for 24 hours and then exposed to cisplatin (0.5 microM) for an additional 72 hours. A cell growth inhibition assay, an apoptosis assay, and an NF-kappaB 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 microg/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 microM genistein with 0.5 microM cisplatin resulted in significantly greater growth inhibition (P < 0.01) and more apoptosis in BxPC-3 cells compared with either agent alone. Preexposure of BxPC-3 cells to genistein abrogated cisplatin-induced activation of NF-kappaB, 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-kappaB was inactivated in genistein-treated animal tumors, whereas cisplatin significantly induced NF-kappaB 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-kappaB activity and contributes toward enhancing the apoptosis-inducing effect of cisplatin, leading to greater antitumor activity in vivo.

美国《癌症》2006, 106(6):1260-1268.

在BxPC3胰腺肿瘤移植瘤中大豆异黄酮染料木黄酮可以增强顺铂诱导的抗肿瘤活性

美国密西根州底特律韦恩州立大学医学院Karmanos癌症研究所血液学和肿瘤学系

背景：

核因子κB（NF-κB）的活化有助于胰腺癌中的耐药性。作者以前表明大豆异黄酮染料木素在体外下调许多癌细胞系中NF-κB的活性。在目前的研究中，他们主要是测试是否NF-κB由染料木素的失活可以增强顺铂诱导的BxPC-3细胞生长抑制和细胞凋亡在体内外的抗肿瘤活性。

方法：

BxPC-3细胞预先暴露于25μM的染料木黄酮24小时，然后暴露于顺铂（0.5μM）72小时。进行细胞生长抑制测定，凋亡测定和NF-kappaB电泳迁移率变动测定。对于体内研究，使用严重联合免疫缺陷小鼠中的BxPC-3细胞的异种移植模型。染料木黄酮以800微克/ kg的剂量口服给予5天，顺铂以9mg/kg的剂量作为腹膜内推注给予，另一组小鼠接受顺铂和染料木黄酮（在第1天给予，染料木黄酮4天）。

结果：

与单独的任一试剂相比，25μM的金雀异黄酮与0.5μM的顺铂的组合导致在BxPC-3细胞中显着更大的生长抑制（P<0.01）和更多的凋亡。BxPC-3细胞暴露于染料木黄酮消除了顺铂诱导的NF-κB活化，这似乎与作者的假说一致。作者还首次证明了染料木黄酮的体内作用增强了顺铂的抗肿瘤活性。对照，染料木黄酮，顺铂和组合的染料木黄酮和顺铂小鼠的肿瘤重量分别为940mg，762mg，261mg和108mg。最重要的是，第一次，作者观察到NF-κB的DNA结合活性在染料木黄酮处理的动物肿瘤中失活，而顺铂显着诱导NF-κBDNA结合活性，并且在染料木黄酮预处理中完全消除肿瘤暴露于顺铂，与体外数据一致。

结论：

总体而言，目前的结果与作者的假说一致，并暗示用染料木黄酮预处理胰腺癌细胞下调NF-kappaB活性并有助于增强顺铂诱导的细胞凋亡作用，导致体内更大的抗肿瘤活性。