Motani Kou, Tabata Keiichi, Kimura Yumiko, Okano Soichiro, Shibata Yasuko, Abiko Yoshimitsu, Nagai Hisashi, Akihisa Toshihiro, Suzuki Takashi
Research Unit of Clinical Medicine, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
Biol Pharm Bull. 2008 Apr;31(4):618-26. doi: 10.1248/bpb.31.618.
Neuroblastoma is the most common solid tumor in children. Despite aggressive chemotherapy, the prognosis of patients with advanced neuroblastoma is still very poor. Our recent study showed that xanthoangelol, a major chalcone constituent of the stem exudates of Angelica keiskei, induced caspase-3-dependent apoptosis in neuroblastoma cells. However, details of the mechanism underlying its apoptotic action are still unclear. Here we show that xanthoangelol triggers oxidative stress by generation of reactive oxygen species and induces apoptosis through release of cytochrome c and activation of caspase-9 in IMR-32 cells. Pretreatment with an antioxidant, vitamin E, prevented the increase of reactive oxygen species and apoptosis induced by xanthoangelol. Proteomic analysis using 2-dimensional electrophoresis and MALDI-TOF-MS revealed that DJ-1 protein was involved in xanthoangelol-induced apoptosis. DJ-1 responded to its oxidative stress status by being oxidized itself. Furthermore, DJ-1 was down-regulated by xanthoangelol, leading to loss of antioxidant function and acceleration of apoptosis. We also show that xanthoangelol has a cytotoxic effect on drug-resistant LA-N-1 and NB-39 cells as well as drug-sensitive IMR-32 and SK-N-SH cells. These findings suggest that xanthoangelol induces apoptosis by increasing reactive oxygen species and targeting DJ-1, and such mechanism may be an effective therapeutic approach for advanced neuroblastoma.
神经母细胞瘤是儿童最常见的实体瘤。尽管采用了积极的化疗，但晚期神经母细胞瘤患者的预后仍然很差。我们最近的研究表明，当归（Angelica keiskei）茎渗出液中的主要查耳酮成分黄当归醇可诱导神经母细胞瘤细胞中依赖半胱天冬酶-3的凋亡。然而，其凋亡作用的潜在机制细节仍不清楚。在此我们表明，黄当归醇通过产生活性氧引发氧化应激，并通过细胞色素c的释放和IMR-32细胞中半胱天冬酶-9的激活诱导凋亡。用抗氧化剂维生素E预处理可防止黄当归醇诱导的活性氧增加和凋亡。使用二维电泳和基质辅助激光解吸电离飞行时间质谱进行的蛋白质组学分析表明，DJ-1蛋白参与了黄当归醇诱导的凋亡。DJ-1通过自身氧化来响应其氧化应激状态。此外，DJ-1被黄当归醇下调，导致抗氧化功能丧失和凋亡加速。我们还表明，黄当归醇对耐药的LA-N-1和NB-39细胞以及药物敏感的IMR-32和SK-N-SH细胞具有细胞毒性作用。这些发现表明，黄当归醇通过增加活性氧和靶向DJ-1诱导凋亡，这种机制可能是晚期神经母细胞瘤的一种有效治疗方法。
