Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.

BACKGROUND: Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. METHODS: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. RESULTS: The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. CONCLUSION: Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.

UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair.

Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials.

GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor of the central nervous system. Despite continuous progression in treatment options for GBM like surgery, radiotherapy, and chemotherapy, this disease still has a high rate of recurrence. The endoplasmic reticulum (ER) stress pathway is associated with chemotherapeutic drug resistance. The UBA1 inhibitor TAK-243 can induce strong ER stress. However, the sensitivity of TAK-243 varies greatly in different tumor cells. This study evaluated the antitumor effects of the GRP78 inhibitor, HA15, combined with TAK-243 on GBM in the preclinical models. HA15 synergistically enhanced the sensitivity of GBM cells to TAK-243. When compared with TAK-243 monotherapy, HA15 combined with TAK-243 significantly inhibited GBM cell proliferation. It also induced G2/M-phase arrest in the cell cycle. In vivo studies showed that HA15 combined with TAK-243 significantly inhibited the growth of intracranial GBM and prolonged survival of the tumor-bearing mice. Mechanistically, HA15 and TAK-243 synergistically activated the PERK/ATF4 and IRE1α/XBP1 signaling axes, thereby eventually activating PARP and the Caspase families, which induced cell apoptosis. Our data provided a new strategy for improving the sensitivity of GBM to TAK-243 treatment and experimental basis for further clinical trials to evaluate this combination therapy.

[Smoking and passive smoking in Chinese, 2002].

OBJECTIVE: To describe the prevalence of smoking, quitting smoke, and passive smoking in different populations by education status, occupation and geographic distribution. METHODS: Surveillance on risk behaviors in 145 disease surveillance points (DSP) was carried out in 2002 by multi-steps random sampling through questionnaires. 16,407 records had been completed with 16 056 used for analysis. Indicators as smoking, current smoking, average cigarettes smoked and the cost per day, etc., were calculated by weight on age proportions from the 2000 census. RESULTS: Ever-smoking rates in males and females aged 15 and over were 66.0% and 3.1%, respectively with ever-smoking rate dropped 1.8% in whole population, but increased in people aged 15-24. The number of total smokers was about 350 million, 30 million more than that in 1996. There were no obvious geographic differences seen among male, but big difference was seen in female smokers. Higher smoking rates were seen in the northeast and northern parts of the country. Rate of quitting smoking was increasing, from 9.42% in 1996 to 11.5% in 2002, referring to an increase of 10 million quitters. However, the rate of no intention to quit among smokers was still very high--74%. The average cigarettes consumption per person-day was the same as that in 1996--14.8 cigarettes/day, which cost 2.73 RBM/day. The cost was various in different groups of population with a 15 times difference. The level of exposure for passive smokers was not improved. The prevalence of passive smoking in nonsmokers were 53% in 1996 and 52% in 2002. Knowledge on smoking and health condition in population had been greatly improved, but still poor in the western areas. 60% of the people claimed in supporting banning of smoking in public places, 45% supporting the banning of all cigarettes ads, but big difference was seen in different geographic areas. CONCLUSION: The prevalence of smoking in Chinese males had reached its peak, leveling but had not yet obvious dropped. Communication on the knowledge of harm in smoking remained weak since people did not understand or support the strategies on tobacco control, especially in the western areas. Data indicated that the prevalence of tobacco use would not decrease over in short period and the disease burden caused by tobacco use would still be heavy in the next 30-50 years. The government and public health authorities should develop effective tobacco control in no time to decrease disease burden caused by smoking and passive smoking.

[The trend and geographic distribution of suicide in Chinese population].

OBJECTIVE: To understand the specific patterns of suicide in Chinese population and its trend. METHODS: The mortality level and trend of suicide in Chinese population by sex, age and areas were reviewed and the geographic distribution of suicide mortality was described using National Disease Surveillance Data in 1991 - 2000. RESULTS: During 1991 - 2000, the mortality rate of suicide was stable. Suicide was still one of the main health problems in Chinese population, especially in rural areas. The pattern of suicide in rural areas remained the same as reported before. The death rate of suicide attempts in female was higher than in male. There was a peak of death rate among rural people aged 15 - 34. However the death rate among rural women aged 15 - 34 was falling, which did not significantly affect the current suicide pattern. CONCLUSIONS: There was high death rate of suicide in eastern and central rural areas, especially in boundaries among provinces, which could have been related to traditional culture, economic situation etc. Using pesticide as a tool of suicide was also an important factor with high death rate of suicide. These findings suggested that the specific pattern would last for another 20 years along with the social development and reform.

[Comparison of data population-based and from hospital-based injuries].

OBJECTIVE: To compare data from an epidemiological survey on injuries with a survey conducted in hospitals on injuries in the same areas and to find out the differences and shortcomings of hospital data in describing the feature of injuries in an area. METHODS: Comparing the causes and age distributions of injuries from the two surveys. RESULTS: The first 4 leading causes of injuries from the population-based survey were mechanical injuries, falls, burns/scalds and traffic accidents while the first 4 leading causes of hospital-based survey were traffic accidents, assault, mechanical injuries and burns/scalds. The differences of the age distributions of these leading causes between the two surveys were significant except mechanical injuries. CONCLUSION: Differences were noticed between population-based survey and hospital-based survey. It should be cautions when using hospital data to describe the features of injuries in a certain area.