Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-κB in BxPC-3 pancreatic cancer cell line
Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-κB in BxPC-3 pancreatic cancer cell line
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DOI：
10.1097/00006676-200405000-00020
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发表时间：
2004-05-01
期刊：
影响因子：
2.9
通讯作者：
Sarkar, FH
中科院分区：
文献类型：
--
作者：
Li, YW;Ellis, KL;Sarkar, FH
肿瘤化疗策略的设计应提供更高的肿瘤反应和联合化疗的低毒性。染料木黄酮已被证明在体外和体内抑制各种癌细胞的生长，而对正常细胞没有毒性。染料木黄酮的抗肿瘤作用可能部分是由于NF-κ B活性的失活。相反，化疗药物无意中诱导NF-κ B活性，这可能导致化疗耐药性。在这项研究中，我们调查是否NF-κ B的失活染料木素将提高化疗药物的疗效。用30 μ mol/L染料木黄酮预处理BxPC-3胰腺癌细胞24小时，然后再暴露于较低浓度的化疗剂24小时。进行细胞生长抑制试验、凋亡试验和NF-κ B EMSA。30 mumol/L金雀异黄素与1 nmol/L多西紫杉醇或100 nmol/L顺铂的组合引起的细胞生长的抑制作用显著大于单独使用任何一种药物。与单药相比，联合治疗诱导BxPC-3细胞凋亡更多。此外，NF-κ B活性在多西他赛或顺铂处理2小时内显著增加，并且在用染料木黄酮预处理的细胞中，这些试剂的NF-κ B诱导活性完全消除。这些结果清楚地表明，金雀异黄素预处理，其灭活NF-κ B活性，连同金雀异黄素的其他细胞效应，可能有助于增加非毒性剂量的多西他赛和顺铂的细胞生长抑制和细胞凋亡诱导作用，这可能是一种新的治疗胰腺癌的策略。
Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-kappaB activity. In contrast, chemotherapeutic agents inadvertently induce NF-kappaB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-kappaB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 mumol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-kappaB EMSA were performed. The combination of 30 mumol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-kappaB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-kappaB-inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-kappaB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.