Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientìficas, Madrid, Spain.
J Pharmacol Exp Ther. 2010 Oct;335(1):114-23. doi: 10.1124/jpet.110.168344. Epub 2010 Jul 6.
Arsenic trioxide (ATO, Trisenox) is an important antileukemic drug, but its efficacy is frequently low when used as a single agent. Here, we demonstrate that the apoptotic action of ATO is greatly increased when combined with subcytotoxic curcumin concentrations in U937 and HL60 human acute myeloid leukemia cells, and with lower efficacy in K562 chronic myelogenous leukemia cells. Curcumin exerts similar cooperative effect with the mitochondria-targeting drug lonidamine, whereas the response is negligible in combination with the DNA-targeting drug cisplatin. Curcumin plus ATO or lonidamine stimulates typical events of the mitochondrial executioner pathway (Bax and Bid activation, cytochrome c release, X-linked inhibitor of apoptosis down-regulation, and caspase-9/-3 activation) and causes mitochondrial transmembrane potential dissipation, which nevertheless represents a late event in the apoptotic response. Curcumin increases anion superoxide production, and its proapoptotic action in combination with ATO and lonidamine is mimicked by pro-oxidant agents (2-methoxyestradiol and H(2)O(2)) and prevented by antioxidant agents [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride and N-acetyl-l-cysteine]. Within the assayed time period (16-24 h), curcumin does not significantly modify p38-mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase phosphorylation/activation or nuclear factor-κB activity, but it greatly stimulates extracellular signal-regulated kinase (ERK) phosphorylation, and decreases Akt phosphorylation. Experiments using mitogen-activated protein kinase kinase/ERK inhibitors [2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126)] and phosphatidylinositol 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) indicate that ERK activation does not mediate and even restrains apoptosis potentiation, whereas Akt down-regulation facilitates apoptosis generation. In summary, cotreatment with curcumin may represent a useful manner of increasing the efficacy of ATO and lonidamine as antitumor drugs in myeloid leukemia cells.
三氧化二砷（ATO，Trisenox）是一种重要的抗白血病药物，但作为单一药物使用时疗效往往较低。在这里，我们证明三氧化二砷与亚细胞毒性姜黄素浓度联合使用时，在 U937 和 HL60 人急性髓系白血病细胞中的凋亡作用大大增强，而在 K562 慢性髓系白血病细胞中的疗效较低。姜黄素与线粒体靶向药物 lonidamine 发挥相似的协同作用，而与 DNA 靶向药物顺铂联合使用时则无明显作用。姜黄素加 ATO 或 lonidamine 刺激线粒体执行器途径的典型事件（Bax 和 Bid 激活、细胞色素 c 释放、X 连锁凋亡抑制剂下调和 caspase-9/-3 激活）并导致线粒体跨膜电位耗散，但这代表凋亡反应的晚期事件。姜黄素增加阴离子超氧化物的产生，其与 ATO 和 lonidamine 联合的促凋亡作用可被促氧化剂（2-甲氧基雌二醇和 H2O2）模拟，并可被抗氧化剂[Mn（III）四（4-苯甲酸）卟啉氯化物和 N-乙酰-L-半胱氨酸]预防。在所测试的时间段（16-24 小时）内，姜黄素不会显著改变 p38-有丝分裂原激活的蛋白激酶和 c-Jun NH2-末端激酶磷酸化/激活或核因子-κB 活性，但会强烈刺激细胞外信号调节激酶（ERK）磷酸化，并降低 Akt 磷酸化。使用丝裂原激活的蛋白激酶激酶/ERK 抑制剂[2'-氨基-3'-甲氧基黄酮（PD98059）和 1,4-二氨基-2,3-二氰基-1,4-双（2-氨基苯基硫）丁二烯（U0126）]和磷脂酰肌醇 3-激酶抑制剂 2-（4-吗啉基）-8-苯基-4H-1-苯并吡喃-4-酮（LY294002）进行的实验表明，ERK 激活不会介导甚至抑制凋亡增强，而 Akt 下调促进凋亡发生。总之，与姜黄素联合治疗可能是增加三氧化二砷和 lonidamine 在髓样白血病细胞中作为抗肿瘤药物疗效的一种有用方法。
