Silibinin Inhibits Glioma Cell Proliferation via Ca(2+)/ROS/MAPK-Dependent Mechanism In Vitro and Glioma Tumor Growth In Vivo
Kim KW, Choi CH, Kim TH, Kwon CH, Woo JS, Kim YK.
Neurochem Res. 2009 Mar 5
Department of Neurosurgery, College of Medicine, Pusan National University, Pusan, 602-739, Korea.
Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanism and in vivo efficacy in glioma were not elucidated. The present study was undertaken to determine the effect of silibinin on glioma cell proliferation in vitro and to examine whether silibinin inhibits tumor growth in vivo. Silibinin resulted in inhibition of proliferation in a dose- and time-dependent manner, which was largely attributed to cell death. Silibinin induced a transient increase in intracellular Ca(2+) followed by an increase in reactive oxygen species (ROS) generation. The silibinin-induced cell death was prevented by EGTA, calpain inhibitor and antioxidants (N-acetylcysteine and Trolox). Western blot analysis showed that silibinin also induced ROS-dependent activation of extracellular signal-regulated kinase, p38 kinase, and c-Jun N-terminal kinase. Inhibitors of these kinases prevented the silibinin-induced cell death. Silibinin caused caspase activation and the silibinin-induced cell death was prevented by caspase inhibitors. Glioma cell migration was also decreased by silibinin treatment. Oral administration of silibinin in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in Ki-67 positive cells, an increase in TUNEL-positive cells, and caspase activation. These results indicate that silibinin induces a caspase-dependent cell death via Ca(2+)/ROS/MAPK-mediated pathway in vitro and inhibits glioma growth in vivo. These data suggest that silibinin may serve as a potential therapeutic agent for malignant human gliomas.
Insomnia drug (zolpidem) can improve brain function
Annals of Neurology Mar 13, 2007 - 9:55:22 AM
A new study reported that zolpidem, a drug normally used to treat insomnia, temporarily improved brain function in a patient suffering from akinetic mutism, a condition in which the person is alert but cannot speak or move. The patient was able to communicate, walk, and eat without assistance after receiving the drug for a bout of insomnia. The study was published in the March 2007 issue of Annals of Neurology, the official journal of the American Neurological Association.
Led by Christine Brefel-Courbon, M.D., of the University Hospital in Toulouse, France, researchers conducted a study of a 48 year-old woman who developed akinetic mutism due to oxygen deprivation to her brain following an attempted suicide by hanging. The patient was totally dependent, unable to speak or walk, and was using a feeding tube for nourishment, although she was able to understand single words. Two years after the suicide attempt, she was given zolpidem for a bout of insomnia; 20 minutes later, she was able to communicate to her family, eat by herself, and move. These effects lasted for up to three hours. After systematically withdrawing all of her medications one by one, it was concluded that the positive effect was due to zolpidem. "This phenomenon was so reproducible that caregivers used to give her up to three tablets each day without sleepiness as ’side effect,’" the authors state.
The researchers systematically assessed the effect of zolpidem on motor and cognitive function and explored its effect on brain activity using positron emission tomography (PET) scans. They administered motor tests such as finger tapping and walking, and language tests such as spontaneous speech, word repetition, and object naming. They also conducted brain imaging studies to assess brain metabolism and cognitive activation using PET scans. All of these were conducted with both zolpidem and a placebo in a randomized, double-blind study.
The results showed that after receiving zolpidem, the patient was able to stand up and walk, repeat words and sentences, read words, and name objects, although she was not able to speak spontaneously. Administration of the drug increased brain metabolism, and PET scans also showed improvement in cerebral areas involved in motivational processing.
Although previous studies have shown the positive effect of zolpidem on catatonic conditions, the authors state, "To our knowledge, this is the first study assessing the impact of zolpidem of post-anoxic brain injury using the modern methodological standards of clinical pharmacology." The authors demonstrated increased brain activity in the frontal cortex, which is associated with higher cognitive performances, with zolpidem. They suggest that the mechanism may be due to an activation of neural circuits in the brain that control movement and verbal expression, but that the lesions that occurred due to oxygen deprivation may have been too severe to allow spontaneous speech. They conclude that single patient trials can be a logical approach to identifying potentially beneficial drugs, especially in the case of rare or orphan diseases.
含有少枝胶质细胞瘤成分胶质母细胞瘤：36例临床分析 Cerebral glioblastoma with oligodendrogliomal component: analysis of 36 cases Journal of Neuro-Oncology, 04/08/09 多形性胶质母细胞瘤中少枝胶质瘤细胞成分的出现是否就预示着病人有一个较好的预后？Salvati M等的研究发现，1p和19q染色体缺失频繁的见于含有少枝胶质瘤细胞成分的多形性胶质母细胞瘤标本中。 450例幕上多形性胶质母细胞瘤已经在在病理学上得到确诊。病人接受了至少是次全的外科手术切除，继而行标准的放化疗治疗。检测到有36例（8%）病人含有少枝胶质瘤成分。这些标本都进行了分子遗传学研究，拟在检测有无1p和19q和10q染色体缺失，EGFR扩增和TP53基因表达。 结论： 含少枝成分组的平均年龄为52.1岁，所有多形性胶质母细胞瘤组的平均年龄为62.4岁； 染色体分析如下：27例(75.0%)病人中可见1p和/或19q缺失；21例病人(58.1%)中可见10q的缺失；14例病人中可见EGFR扩增(39%)；8例病人(22.2%)可见TP53突变。 含少枝成分组的无进展期为10.3个月，而所有多形性胶质母细胞瘤组是7.6个月。 含少枝成分组的总生存期为20.9个月，而所有多形性胶质母细胞瘤组的生存期为13.6个月。 Salvati M et al. - In a study to assess whether observation of oligodendroglial foci within glioblastoma multiforme (GBM) samples and their correlation with genetic alterations may predict a better prognosis, it was found that the presence of an oligodendroglial component in GBM appears to be an important prognostic factor to which better prognosis can be related. LOH 1p and 19q was significantly associated with GBM with oligodendroglial component. Methods • 450 pts affected by histologically proven supratentorial cerebral GBM were treated. • Pts received at least subtotal surgical removal, followed by the same standard radio-chemotherapy adjuvant treatment. • In a subgroup of 36 pts (8.0%), an oligodendroglial component was observed. • Molecular assessment of these cases was performed and LOH for 1p, 19q and 10q, EGFR amplification and TP53 gene expression was determined. Results • Median age of this subgroup was 52.1 yrs vs 62.4 yrs in the entire GBM population. • Chromosome analysis resulted as follows: LOH 1p and/or 19q in 27 cases (75.0%), LOH of 10q in 21 cases (58.1%), EGFR amplification in 14 cases (39%), and TP53 mutation in 8 pts (22.2%). • OS was of 20.9 mos while it was 13.6 mos in the entire GBM population. • Progression free survival was 10.3 mos and 7.6 mos for the entire group. • 2-yr survival was of 55%.
Veelen回顾总结了90例经过手术确诊的低度恶性星形细胞瘤病人资料，分析后认为，以癫痫发作为唯一症状的幕上低度恶性星形细胞瘤患者，要比那些伴有其它症状的患者预后要好。这种预后并不被手术的时间所影响。作者认为对此类疑似病人，可以安全的推迟手术时间，直到出现临床或者影像上进展后再次手术干预，也是合理的选择。 Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and... Title Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery Authors Veelen, van, M.L.C.; Avezaat, C.J.J.; Kros, J.M.; Putten, van, W.; Vecht, C. Date 1998-01-01 Summary BACKGROUND: A retrospective study of patients with low grade astrocytoma was carried out because the best management of such patients remains controversial. Prognostic factors were identified by multivariate analysis. Special attention was paid to the effect of extent and timing of surgery. METHODS: Ninety patients with low grade astrocytoma were studied. Seventy two patients had resective surgery, 15 had a diagnostic biopsy only, and three patients had resective surgery after initial biopsy. RESULTS: Significant prognostic factors for survival were age, preoperative neurological condition, epilepsy as the single sign, extent of surgery, and histology. The extent of surgery was highly significant on univariate analysis (p=0.002); however, after correction for age and preoperative symptoms this was considerably reduced (p=0.04). A subgroup of 30 patients with epilepsy as their single presenting symptom was identified. Thirteen of these patients were treated immediately after diagnosis, whereas the other 17 patients were initially followed up and treated only after clinical or radiological progression. Survival in both groups was identical (63% survival rate after five years) and much better than survival for the whole group (27% survival rate after five years). Malignant dedifferentiation was observed in 25 (70%) of 36 patients who were reoperated, after a median period of 37 months. This period was 41 months for the subgroup of patients with epilepsy only and 28 months for the remaining patients. CONCLUSIONS: Due to the retrospective nature of the study only restricted conclusions can be drawn. Low grade glioma with epilepsy as the single symptom has a much better prognosis than if accompanied by other symptoms. This prognosis is not influenced by the timing of surgery. It seems, therefore, safe to defer surgery until clinical or radiological progression in low grade glioma with epilepsy only.
多形性胶质母细胞瘤 Glioblastoma Multiforme 本文出处：http://www.svmh.com/health/content.aspx?chunkiid=102896 (GBM; Brain Tumor; Malignant Astrocytoma) Pronounced: GLEE-oh-blass-TOE-mah by Sonja Lyons En Español (Spanish Version)More InDepth Information on This Condition
Definition 定义 Glioblastoma multiforme (GBM) is the most common glioma (a type of brain cancer). It represents nearly one fourth of all primary brain tumors. This cancer starts in the glial cells, which are cells that help nerve cells work. 最常见的胶质瘤，大约占原发性脑肿瘤的1/4。它起源于胶质细胞，这是帮助神经元进行正常工作的一类细胞。 This condition can develop spontaneously. Less commonly, it can develop from a lower grade, less malignant (cancerous) brain tumor. Most cases are located in the cerebral hemisphere, but the cancer can begin in the spinal cord or brain stem. 此瘤常自发形成。少见的情况下，可由低度恶性的脑肿瘤发展而来。大部分位于大脑半球，但也可起源于脊髓和脑干。 If you suspect you have this serious condition, contact your doctor immediately. Early treatment leads to a more favorable outcome. 如果你有这种比较严重的情况出现，要立即联系自己的保健医生。早期治疗可能会导致一个较好的预后。
Causes 病因 GBM originates from astrocytes, which are a type of glial cell. The factors that cause normal-functioning astrocytes to become cancerous is not well understood. 多形性胶质母细胞瘤起源于星形胶质细胞，这是胶质细胞的一种。促使正常工作的星形胶质细胞转变为肿瘤细胞的原因尚不得而知。
Risk Factors 危险因素 These factors increase your chance of developing GBM. Tell your doctor if you have any of these risk factors: 如下的因素可能会增加你发展为多形性胶质母细胞瘤的可能，如果有此类的状况请及时告知你的医生：
1. Sex: male (slightly more common in men that women) 性别：男性稍多于女性 2. Age: over 50 years old 年龄：大于50岁 3. Ethnicity: Caucasians, Latinos, Asians 种族：高加索人，拉丁美洲人，亚洲人 4. Having a low-grade astrocytoma (brain tumor), which occasionally develops into a higher-grade tumor 已经患有低度星形细胞瘤，偶尔会转变为高度恶性胶质瘤 5. Having one of the following genetic disorders is associated with an increased incidence of gliomas 有如下遗传学疾病的人患胶质瘤的可能性增加 6. Neurofibromatosis 神经纤维瘤病 7. Tuberous sclerosis 结节性硬化 8. Von Hippel-Lindau disease 脑视网膜血管瘤病 9. Li-Fraumeni syndrome 李弗劳明综合征(p53基因有突变) 10. Turcot’s syndrome 特科特(氏)综合征:结肠息肉-脑肿瘤综合征 11. Radiotherapy (association between high-dose ionizing radiation and astrocytoma) 放疗病史（大剂量的离子照射会导致星形细胞瘤） There is inconsistent evidence that electromagnetic radiation and cell phone use are associated with this condition. 目前电磁辐射以及手机使用和胶质瘤的关系尚不明确。 Symptoms 症状 Symptoms include: 症状包括
1. New onset headaches—more than 30% of patients 新近出现的头痛——大于30%的病人会出现 2. New onset seizures—20% to 30% patients 新近出现的癫痫发作——20-30%的病人会出现 3. Progressive cognitive dysfunction—depends on the location of the tumor; problems with vision, language, motor function, or sensation may occur 进行性发展的认知功能障碍——和肿瘤部位有关，涉及视力视野变化，语言变化，运动功能或者感觉方面的异常 4. Personality changes 性格改变 5. Behavioral changes, development of inappropriate behaviors 行为改变，不合适行为的发展 6. Memory loss 记忆丧失
Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y. Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme’s affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, alpha-ketoglutarate (alpha-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by alpha-KG. The rise in HIF-1alpha levels was reversible by an alpha-KG derivative. HIF-1alpha levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.