Proteomic Analysis of Apoptosis Induced by Xanthoangelol, a Major Constituent of Angelica keiskei, in Neuroblastoma

Abstract

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.

New 4-Maleamic Acid and 4-Maleamide Peptidyl Chalcones as Potential Multitarget Drugs for Human Prostate Cancer

“…Their mechanisms of action involve the tubulin assembly inhibition, antiangiogenic effects, reactive oxygen species generation, and apoptosis induction through the release of cytochrome c and activation of caspase-9 and the inhibition of the nuclear factor kappa B survival system (7,8,26,27). More recent studies have shown the effect of different chalcones on PCa, demonstrating substantial in vitro anti-proliferative activities in LNCaP and PC-3 human prostate cancer cell lines as antagonists of androgen receptors (28).…”

Changes in the two‐dimensional electrophoresis pattern of the Parkinson's disease related protein DJ‐1 in human SH‐SY5Y neuroblastoma cells after dopamine treatment

“…2A). Each spot was observed to be present in all replicates and under both experimental conditions, although the relative intensity of the most acidic (22) and most basic (2) spot was significantly affected by dopamine treatment (Fig. 2B and C).…”

“…Figure 2D shows a meta-gel, i.e. an average intensity projection image, wherein each pixel stores the average intensity in the six original images at corresponding pixel location (8,13,21,22). The color scale of this meta-gel accounts for the occurrence frequency of each spot in the considered experiments, with less frequent spot positions in blue and more frequent spot positions in white.…”

Dietary chalcones with chemopreventive and chemotherapeutic potential

“…Thus, mitochondria serve as novel cellular targets for naturally occurring anticancer drugs [163]. In addition, apoptosis induction through ROS generation by xanthoangelol (33), a major constituent of Angelica keiskei, was described by Motani et al in neuroblastoma [121]. Another component of this plant, isobavachalcone (15), induced apoptosis in neuroblastoma by downregulation of pro-caspase 3 and 9 followed by upregulation of cleaved caspase 3 and 9 and Bax induction, similar to the effects of chalcone (10) in human bladder cancer cells [128,158].…”