Department of Anesthesiology, University of Colorado Denver, Aurora, CO, USA.
Int J Cancer. 2011 Dec 15;129(12):2945-57. doi: 10.1002/ijc.25965. Epub 2011 Apr 20.
Bezielle is an orally administered aqueous extract of Scutellaria barbata for treatment of advanced and metastatic breast cancer. Phase I trials showed promising tolerability and efficacy. In our study, we used a combined proteomic-metabolomic approach to investigate the molecular pathways affected by Bezielle in ER-positive BT474 and ER-negative SKBR3 cell lines. In both, Bezielle inhibited cell proliferation, induced cell death and G2 cycle arrest by regulating the mediator proteins Jab1, p27(Kip1) and p21(Cip1) . In addition, it stimulated reactive oxygen species production, hyperactivation of PARP and inhibition of glycolysis. Bezielle's ability to induce oxidative stress was associated with the changes in expression of redox potential maintaining enzymes: glutathione- and thioredoxin-related proteins and peroxiredoxins. In regards to cell metabolism, decreased expression of α-enolase was associated with a reduction of de novo (13) C-lactate formation. Reduced Krebs cycle activity as evidenced by the reduced expression of α-ketoglutarate dehydrogenase and succinyl-CoA synthetase led to decreased intracellular succinate concentrations. By inhibiting glucose metabolism, cells reacted by lowering the expression of glucose transporters and resulting in decreased intracellular glucose concentration. Decreased expression of fatty acid synthase and reduced concentration of phosphocholine indicated considerable changes in phospholipid metabolism. Ultimately, by inhibiting the major energy-producing pathways, Bezielle caused depletion of ATP and NAD(H). Both cell lines were responsive, thus suggesting that Bezielle has the potential to be effective against ER-negative breast cancers. In conclusion, Bezielle's cytotoxicity toward cancer cells is primarily based on inhibition of metabolic pathways that are preferentially activated in tumor cells thus explaining its specificity for cancer cells.
贝泽利是一种口服的黄芩水提物，用于治疗晚期和转移性乳腺癌。I 期临床试验显示出良好的耐受性和疗效。在我们的研究中，我们使用了一种联合蛋白质组学-代谢组学方法来研究贝泽利对 ER 阳性 BT474 和 ER 阴性 SKBR3 细胞系影响的分子途径。在这两种细胞中，贝泽利通过调节介体蛋白 Jab1、p27(Kip1)和 p21(Cip1)，抑制细胞增殖，诱导细胞死亡和 G2 期细胞周期阻滞。此外，它还刺激活性氧的产生、PARP 的过度激活和糖酵解的抑制。贝泽利诱导氧化应激的能力与氧化还原电势维持酶表达的变化有关：谷胱甘肽和硫氧还蛋白相关蛋白和过氧化物酶。关于细胞代谢，α-烯醇酶表达的降低与从头 (13)C-乳酸形成的减少有关。三羧酸循环活性的降低，表现为α-酮戊二酸脱氢酶和琥珀酰辅酶 A 合成酶表达的降低，导致细胞内琥珀酸浓度降低。通过抑制葡萄糖代谢，细胞通过降低葡萄糖转运蛋白的表达和降低细胞内葡萄糖浓度来做出反应。脂肪酸合酶表达的降低和磷酸胆碱浓度的降低表明磷脂代谢发生了相当大的变化。最终，通过抑制主要的能量产生途径，贝泽利导致了 ATP 和 NAD(H)的消耗。两种细胞系都有反应，因此表明贝泽利有可能对 ER 阴性乳腺癌有效。总之，贝泽利对癌细胞的细胞毒性主要基于对代谢途径的抑制，这些代谢途径在肿瘤细胞中优先激活，从而解释了其对癌细胞的特异性。
