College of Biophotonics, South China Normal University, Guangzhou, China.
Int J Cancer. 2010 Jul 15;127(2):462-73. doi: 10.1002/ijc.25044.
NF-kappaB activation is known to reduce the efficiency of chemotherapy in cancer treatment. Ursolic acid, a minimally toxic compound, has shown the capability to inhibit NF-kappaB activation in living cells. Here, for the first time, we investigated the effects and mechanisms of NF-kappaB inhibition by ursolic acid on chemotherapy treatment (Taxol or cisplatin) of cancer. ASTC-a-1 (human lung adenocarcinoma), Hela (human cervical cancer) cells, primary normal mouse cells of lung and liver and mouse in vivo model were used. Activity of signal factors (NF-kappaB, Akt, Fas/FasL, BID, Bcl-2, cytochrome c and caspase-8, 3) was used to analyze the mechanisms of ursolic acid-chemo treatment. Ursolic acid-mediated suppression of NF-kappaB drastically reduced the required dosage of the chemotherapeutic agents to achieve identical biological endpoints and enhanced the chemotherapeutic agent-induced cancer cells apoptosis. Chemosensitization by ursolic acid in cancer cells was dependent on the amplified activation of intrinsic pathway (caspase-8-BID-mitochondria-cytochrome c-caspase-3) by augmentation of BID cleavage and activation of Fas/FasL-caspase-8 pathway. Prolonged treatment with relatively low doses of ursolic acid also sensitized cancer cells to the chemotherapeutic agents through suppression of NF-kappaB. Chemosensitization by ursolic acid was observed only in cancer cells, but not in primary normal cells. The inhibitive effect of ursolic acid on NF-kappaB was reversible, and the reversal was not accompanied by a loss in cells viability. By supplementing chemotherapy with minimally toxic ursolic acid, it is possible to improve the efficacy of cancer treatment by significantly reducing the necessary drug dose without sacrificing the treatment results.
NF-κB 的激活被认为会降低癌症治疗中化疗的效率。熊果酸是一种低毒性的化合物，已显示出抑制活细胞中 NF-κB 激活的能力。在这里，我们首次研究了熊果酸抑制 NF-κB 对癌症化疗（紫杉醇或顺铂）的影响和机制。使用了 ASTC-a-1（人肺腺癌）、Hela（人宫颈癌）细胞、肺和肝的原代正常小鼠细胞以及小鼠体内模型。信号因子（NF-κB、Akt、Fas/FasL、BID、Bcl-2、细胞色素 c 和 caspase-8、3）的活性用于分析熊果酸-化疗治疗的机制。熊果酸介导的 NF-κB 抑制作用大大降低了实现相同生物学终点所需的化疗药物剂量，并增强了化疗药物诱导的癌细胞凋亡。熊果酸在癌细胞中的化疗增敏作用依赖于内在途径（caspase-8-BID-线粒体-细胞色素 c-caspase-3）的放大激活，通过增强 BID 切割和 Fas/FasL-caspase-8 途径的激活来实现。用相对低剂量的熊果酸进行长期治疗也通过抑制 NF-κB 使癌细胞对化疗药物敏感。熊果酸的化疗增敏作用仅在癌细胞中观察到，而在原代正常细胞中未观察到。熊果酸对 NF-κB 的抑制作用是可逆的，逆转时不会导致细胞活力丧失。通过用低毒性的熊果酸补充化疗，可以在不牺牲治疗效果的情况下，通过显著降低所需药物剂量来提高癌症治疗的疗效。
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