Cancer Research, 2005, 65(15):6934.

Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells

Yiwei Li,Philip A. Philip, et al

Departments of 1Pathology and 2Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor kappaB (NF-kappaB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-kappaB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-kappaB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 micromol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 micromol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-kappaB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-kappaB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-kappaB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-kappaB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.

美国《癌症研究》，2005年

大豆异黄酮金雀异黄素导致的核因子κB的失活有助于人类癌细胞中由化学治疗剂诱导的细胞凋亡增加

李义伟，菲利普 A. 菲利普，等

密歇根州底特律韦恩州立大学医学院病理学和内科，卡尔莫斯癌症研究所

癌症化疗策略通常需要多种药物。然而，使用多种药物会增加毒性，导致治疗结果不佳。因此，必须优化联合化疗以增加肿瘤反应，同时降低其毒性。已知化疗剂在肿瘤细胞中诱导核因子κB（NF-κB）活性，导致细胞杀伤和耐药性降低。相比之下，染料木素已经显示出抑制NF-κB的活性和各种癌细胞的生长而不引起全身毒性。因此，我们研究了使用化疗药物处理各种癌细胞之前，染料木黄酮对NF-κB的失活是否会导致更好的肿瘤细胞杀伤，如使用基因转染的体外研究和动物研究所测试的。 PC-3（前列腺），MDA-MB-231（乳腺），H460（肺）和BxPC-3（胰腺）癌细胞用15-30微摩尔/ L染料木黄酮预处理24小时，然后暴露于低剂量化疗剂另外48至72小时。我们发现15-30微摩尔/ L染料木素与100至500nmol / L顺铂，0.5至2nmol / L多西紫杉醇或50ng / mL多柔比星联合，导致与任一种药物相比，细胞生长和凋亡诱导程度显着更大单独。此外，我们发现顺铂和多西紫杉醇治疗2小时内NF-κB活性显着增加，并且这些药物的NF-κB诱导活性在用染料木素预处理的细胞中被完全消除。这些结果也首次通过动物实验，p65 cDNA转染和p65小干扰RNA研究得到支持，这清楚地表明特异性靶标（NF-kappaB）在体内受到影响。总的来说，我们的研究结果清楚地表明，染料木黄酮预处理使NF-κB失活，并且可能有助于增加前列腺，乳腺，肺和胰腺癌细胞中顺铂，多西紫杉醇和多柔比星诱导的生长抑制和细胞凋亡。这些结果需要精心设计的临床研究调查大豆异黄酮和常用的化学治疗剂用于治疗人类癌症的组合。