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Sun XF, Luo WC, Huang SQ, Zheng YJ, Xiao L, Zhang ZW, Liu RH, Zhong ZW, Song JQ, Nan K, Qiu ZX, Zhong J, Miao CH. Immune-cell signatures of persistent inflammation, immunosuppression, and catabolism syndrome after sepsis. MED 2025; 6:100569. [PMID: 39824181 DOI: 10.1016/j.medj.2024.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 10/13/2024] [Accepted: 12/12/2024] [Indexed: 01/20/2025]
Abstract
BACKGROUND Management of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) after sepsis remains challenging for patients in the intensive care unit, experiencing poor quality of life and death. However, immune-cell signatures in patients with PICS after sepsis remain unclear. METHODS We determined immune-cell signatures of PICS after sepsis at single-cell resolution. Murine cecal ligation and puncture models of PICS were applied for validation. FINDINGS Immune functions of two enriched monocyte subpopulations, Mono1 and Mono4, were suppressed substantially in patients with sepsis and were partially restored in patients with PICS after sepsis and exhibited immunosuppressive and pro-apoptotic effects on B and CD8T cells. Patients with PICS and sepsis had reduced naive and memory B cells and proliferated plasma cells. Besides, naive and memory B cells in patients with PICS showed an active antigen processing and presentation gene signature compared to those with sepsis. PICS patients with better prognoses exhibited more active memory B cells and IGHA1-plasma cells. CD8TEMRA displayed signs of proliferation and immune dysfunction in the PICS-death group in contrast with the PICS-alive group. Megakaryocytes proliferation was more pronounced in patients with PICS and sepsis than in healthy controls, with notable changes in the anti-inflammatory and immunomodulatory effects observed in patients with PICS and verified in mice models. CONCLUSIONS Our study evaluated PICS after sepsis at the single-cell level, identifying the heterogeneity present within immune-cell subsets, facilitating the prediction of disease progression and the development of effective intervention. FUNDING This work was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission "Yiyuan New Star" Youth Medical Talent Cultivating Program, and Shanghai Clinical Research Center for Anesthesiology.
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Affiliation(s)
- Xing-Feng Sun
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Anesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200438, China
| | - Wen-Chen Luo
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Shao-Qiang Huang
- Department of Anesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200438, China
| | - Yi-Jun Zheng
- Department of Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Lei Xiao
- The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, and the Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Zhong-Wei Zhang
- Department of Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Rong-Hua Liu
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Zi-Wen Zhong
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Jie-Qiong Song
- Department of Critical Care Medicine, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Ke Nan
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China
| | - Zhi-Xin Qiu
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Department of Anesthesiology, Zhongshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 200032, China.
| | - Jing Zhong
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China.
| | - Chang-Hong Miao
- Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China; Laboratory of Perioperative Stress and Protection, Shanghai 200032, China.
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Yuan Y, Su Y, Wu Y, Xue Y, Zhang Y, Zhang Y, Zheng M, Chang T, Qu Y, Zhao T. Knowledge structure and hotspots research of glioma immunotherapy: a bibliometric analysis. Front Oncol 2023; 13:1229905. [PMID: 37671057 PMCID: PMC10476340 DOI: 10.3389/fonc.2023.1229905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 08/03/2023] [Indexed: 09/07/2023] Open
Abstract
Background Glioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis. Method Publications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications. Results A total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot. Conclusion Using a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future.
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Affiliation(s)
- Yexin Yuan
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yue Su
- Department of Neurology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yingxi Wu
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yafei Xue
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yunze Zhang
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yangyang Zhang
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Min Zheng
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Ting Chang
- Department of Neurology, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Yan Qu
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Tianzhi Zhao
- Department of Neurosurgery, Tangdu Hospital, Air Force Medical University, Xi’an, Shaanxi, China
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Manunu B, Serafin AM, Akudugu JM. BAG1, MGMT, FOXO1, and DNAJA1 as potential drug targets for radiosensitizing cancer cell lines. Int J Radiat Biol 2023; 99:292-307. [PMID: 35511481 DOI: 10.1080/09553002.2022.2074164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND PURPOSE Activation of some signaling pathways can promote cell survival and have a negative impact on tumor response to radiotherapy. Here, the role of differences in expression levels of genes related to the poly(ADP-ribose) polymerase-1 (PARP-1), heat shock protein 90 (Hsp90), B-cell lymphoma 2 (Bcl-2), and phosphoinositide 3-kinase (PI3K) pathways in the survival or death of cells following X-ray exposure was investigated. METHODS Eight human cell cultures (MCF-7 and MDA-MB-231: breast cancers; MCF-12A: apparently normal breast; A549: lung cancer; L132: normal lung; G28, G44 and G112: glial cancers) were irradiated with X-rays. The colony-forming and real-time PCR based on a custom human pathway RT2 Profiler PCR Array assays were used to evaluate cell survival and gene expression, respectively. RESULTS The surviving fractions at 2 Gy for the cell lines, in order of increasing radioresistance, were found to be as follows: MCF-7 (0.200 ± 0.011), G44 (0.277 ± 0.065), L132 (0.367 ± 0.023), MDA-MB-231 (0.391 ± 0.057), G112 (0.397 ± 0.113), A549 (0.490 ± 0.048), MCF-12A (0.526 ± 0.004), and G28 (0.633 ± 0.094). The rank order of radioresistance at 6 Gy was: MCF-7 < L132 < G44 < MDA-MB-231 < A549 < G28 < G112 < MCF-12A. PCR array data analysis revealed that several genes were differentially expressed between irradiated and unirradiated cell cultures. The following genes, with fold changes: BCL2A1 (21.91), TP53 (8743.75), RAD51 (11.66), FOX1 (65.86), TCP1 (141.32), DNAJB1 (3283.64), RAD51 (51.52), and HSPE1 (12887.29) were highly overexpressed, and BAX (-127.21), FOX1 (-81.79), PDPK1 (-1241.78), BRCA1 (-8.70), MLH1 (-12143.95), BCL2 (-18.69), CCND1 (-46475.98), and GJA1 (-2832.70) were highly underexpressed in the MDA-MB-231, MCF-7, MCF-12A, A549, L132, G28, G44, and G112 cell lines, respectively. The radioresistance in the malignant A549 and G28 cells was linked to upregulation in the apoptotic, DNA repair, PI3K, and Hsp90 pathway genes BAG1, MGMT, FOXO1, and DNAJA1, respectively, and inhibition of these genes resulted in significant radiosensitization. CONCLUSIONS Targeting BAG1, MGMT, FOXO1, and DNAJA1 with specific inhibitors might effectively sensitize radioresistant tumors to radiotherapy.
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Affiliation(s)
- Bayanika Manunu
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - Antonio M Serafin
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - John M Akudugu
- Division of Radiobiology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
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CD95 gene deletion may reduce clonogenic growth and invasiveness of human glioblastoma cells in a CD95 ligand-independent manner. Cell Death Dis 2022; 8:341. [PMID: 35906203 PMCID: PMC9338300 DOI: 10.1038/s41420-022-01133-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/24/2022]
Abstract
CD95 (Fas/APO-1) is a multifunctional cell surface receptor with antithetic roles. First described to mediate cell death, interactions of CD95 with its natural ligand, CD95L, have also been described to induce tumor-promoting signaling leading to proliferation, invasion and stem cell maintenance, mainly in cancer cells that are resistant to CD95-mediated apoptosis. While activation of CD95-mediated apoptosis in cancer cells may not be clinically practicable due to toxicity, inhibition of tumor-promoting CD95 signaling holds therapeutic potential. In the present study, we characterized CD95 and CD95L expression in human glioma-initiating cells (GIC), a glioblastoma cell population with stem cell features, and investigated the consequences of CRISPR-Cas9-mediated CD95 or CD95L gene deletion. In vitro, GIC expressed CD95 but not CD95L and were sensitive to CD95-mediated apoptosis. Upon genetic deletion of CD95, GIC acquired resistance to CD95L-induced apoptosis but exhibited inferior clonogenic growth, sphere-forming capacity, and invasiveness compared with control cells, suggesting the existence of CD95L-independent constitutive CD95 signaling with tumor-promoting properties in GIC. In vivo, GIC expressed CD95 and a non-canonical form of CD95L lacking the CD95-binding region. CD95 genetic deletion did not prolong survival in immunocompromised GIC-bearing mice. Altogether, these data indicate that canonical CD95L may not be expressed in human GIC and suggest the existence of a CD95L-independent CD95-signaling pathway that maintains some malignancy traits of GIC. The lack of altered survival of tumor-bearing mice after genetic deletion of CD95 suggests that CD95 signaling is not essential to maintain the growth of human GIC xenografted into the brains of nude mice. The ligand-independent tumor-promoting role of constitutive CD95 in our GIC models in vitro highlights the complexity and challenges associated with targeting CD95 with therapeutic intent.
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5
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Tumors and Cytomegalovirus: An Intimate Interplay. Viruses 2022; 14:v14040812. [PMID: 35458542 PMCID: PMC9028007 DOI: 10.3390/v14040812] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/19/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
Human cytomegalovirus (HCMV) is a herpesvirus that alternates lytic and latent infection, infecting between 40 and 95% of the population worldwide, usually without symptoms. During its lytic cycle, HCMV can result in fever, asthenia, and, in some cases, can lead to severe symptoms such as hepatitis, pneumonitis, meningitis, retinitis, and severe cytomegalovirus disease, especially in immunocompromised individuals. Usually, the host immune response keeps the virus in a latent stage, although HCMV can reactivate in an inflammatory context, which could result in sequential lytic/latent viral cycles during the lifetime and thereby participate in the HCMV genomic diversity in humans and the high level of HCMV intrahost genomic variability. The oncomodulatory role of HCMV has been reported, where the virus will favor the development and spread of cancerous cells. Recently, an oncogenic role of HCMV has been highlighted in which the virus will directly transform primary cells and might therefore be defined as the eighth human oncovirus. In light of these new findings, it is critical to understand the role of the immune landscape, including the tumor microenvironment present in HCMV-harboring tumors. Finally, the oncomodulatory/oncogenic potential of HCMV could lead to the development of novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies and new therapeutic approaches are actively needed, particularly to fight tumors of poor prognosis.
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El Baba R, Herbein G. Immune Landscape of CMV Infection in Cancer Patients: From "Canonical" Diseases Toward Virus-Elicited Oncomodulation. Front Immunol 2021; 12:730765. [PMID: 34566995 PMCID: PMC8456041 DOI: 10.3389/fimmu.2021.730765] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/23/2021] [Indexed: 11/13/2022] Open
Abstract
Human Cytomegalovirus (HCMV) is an immensely pervasive herpesvirus, persistently infecting high percentages of the world population. Despite the apparent robust host immune responses, HCMV is capable of replicating, evading host defenses, and establishing latency throughout life by developing multiple immune-modulatory strategies. HCMV has coexisted with humans mounting various mechanisms to evade immune cells and effectively win the HCMV-immune system battle mainly through maintaining its viral genome, impairing HLA Class I and II molecule expression, evading from natural killer (NK) cell-mediated cytotoxicity, interfering with cellular signaling, inhibiting apoptosis, escaping complement attack, and stimulating immunosuppressive cytokines (immune tolerance). HCMV expresses several gene products that modulate the host immune response and promote modifications in non-coding RNA and regulatory proteins. These changes are linked to several complications, such as immunosenescence and malignant phenotypes leading to immunosuppressive tumor microenvironment (TME) and oncomodulation. Hence, tumor survival is promoted by affecting cellular proliferation and survival, invasion, immune evasion, immunosuppression, and giving rise to angiogenic factors. Viewing HCMV-induced evasion mechanisms will play a principal role in developing novel adapted therapeutic approaches against HCMV, especially since immunotherapy has revolutionized cancer therapeutic strategies. Since tumors acquire immune evasion strategies, anti-tumor immunity could be prominently triggered by multimodal strategies to induce, on one side, immunogenic tumor apoptosis and to actively oppose the immune suppressive microenvironment, on the other side.
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Affiliation(s)
- Ranim El Baba
- Department Pathogens & Inflammation-EPILAB EA4266, University of Franche-Comté UBFC, Besançon, France
| | - Georges Herbein
- Department Pathogens & Inflammation-EPILAB EA4266, University of Franche-Comté UBFC, Besançon, France
- Department of Virology, Centre hospitalier régional universitaire de Besançon (CHRU) Besançon, Besancon, France
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7
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Mei X, Chen Y, Gan D, Chen Y, Wang L, Cao Y, Wu Z, Liu W, Zhao C, Lin M, Yang T, Hu J. Effect of nucleolin on adriamycin resistance via the regulation of B-cell lymphoma 2 expression in Burkitt's lymphoma cells. J Cell Physiol 2019; 234:22666-22674. [PMID: 31127617 PMCID: PMC6771757 DOI: 10.1002/jcp.28833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 01/26/2023]
Abstract
Nucleolin (NCL, C23) is an important nucleocytoplasmic multifunctional protein. Due to its multifaceted profile and high expression in cancer, NCL is considered to be a marker of drug resistance associated with chemotherapy. However, the biochemical mechanisms in which NCL suppresses drug sensitivity in several cancers have yet to be fully elucidated. This study aims to explore the effect of NCL on drug sensitivity and its potential mechanism in CA46 Burkitt's lymphoma (BL) cells. CA46 BL cells were transfected with lentiviruses carrying the NCL gene (CA46-NCL-overexpression, CA46-NCL-OE), or shRNA sequences that target the endogenous NCL gene (CA46-NCL-knockdown, CA46-NCL-KD). Adriamycin (ADM) IC50 levels for CA46-NCL-overexpressed (OE), CA46-NCL-OE control (OEC), CA46-NCL-knockdown (KD), and CA46-NCL-KD control (KDC) cells were 0.68 ± 0.06 μg/ml, 0.68 ± 0.06 μg/ml, 0.68 ± 0.06 μg/ml, and 0.30 ± 0.04 μg/ml, respectively. Apoptosis rates were significantly increased following NCL KD, whereas the opposite effect was noted in OE cells. A significant reduction of B-cell lymphoma 2 (Bcl-2) mRNA and protein levels in KD cells was observed, while OE cells displayed the opposite effect. The stability of Bcl-2 mRNA was influenced by NCL levels, the half-life of which was extended after NCL-OE, whereas it was reduced in KD cells. Finally, results of RNA-immunoprecipitation assays indicated that NCL could bind to Bcl-2 mRNA in CA46 cells. Taken together, these results suggested that NCL could mediate Bcl-2 expression and stability, and thus enhance ADM resistance in CA46 BL cells.
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Affiliation(s)
- Xuqiao Mei
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
- Department of Clinical LaboratoryThe Affiliated Zhangzhou Municipal Hospital, Fujian Medical UniversityZhangzhouFujianChina
| | - Yanxin Chen
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Donghui Gan
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
- Department of HematologyThe Affiliated Hospital of Putian UniversityPutianFujianChina
| | - Yingyu Chen
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Lingyan Wang
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Yanqin Cao
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Zhengjun Wu
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Weijuan Liu
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Chenxing Zhao
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Minhui Lin
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Ting Yang
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
| | - Jianda Hu
- Fujian Provincial Key Laboratory of HematologyFujian Institute of Hematology, Fujian Medical University Union HospitalFuzhouFujianChina
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Al-Akra L, Bae DH, Leck LYW, Richardson DR, Jansson PJ. The biochemical and molecular mechanisms involved in the role of tumor micro-environment stress in development of drug resistance. Biochim Biophys Acta Gen Subj 2019; 1863:1390-1397. [PMID: 31202693 DOI: 10.1016/j.bbagen.2019.06.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Multi-drug resistance (MDR) is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Moreover, the tumor micro-environment is essential to the formation of drug resistant cancers. Recent evidence indicates that the tumor micro-environment is a critical regulator of cancer progression, distant metastasis and acquired resistance of tumors to various therapies. Despite significant advances in chemotherapy and radiotherapy, the development of therapeutic resistance leads to reduced drug efficacy. SCOPE OF REVIEW This review highlights mechanistic aspects of the biochemistry of the tumor micro-enviroment, such as the hypoglycaemia, reactive oxygen species (ROS), hypoxia and their effects in propagating MDR. This is achieved through: (A) increased survival via autophagy and failure of apoptosis; (B) altered metabolic processing; and (C) reduction in drug delivery and uptake or increased drug efflux. MAJOR CONCLUSIONS The development of MDR in cancer has been demonstrated to be majorly influenced by naturally occurring stressors within the tumor micro-environment, as well as chemotherapeutics. Thus, the tumor micro-environment is currently emerging as a major focus of research which needs to be carefully addressed before cancer can be successfully treated. GENERAL SIGNIFICANCE Elucidating the biochemical mechanisms which promote MDR is essential in development of effective therapeutics that can overcome these acquired defences in cancer cells.
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Affiliation(s)
- Lina Al-Akra
- Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, New South Wales 2006, Australia
| | - Dong-Hun Bae
- Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, New South Wales 2006, Australia
| | - Lionel Y W Leck
- Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, New South Wales 2006, Australia
| | - Des R Richardson
- Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, New South Wales 2006, Australia
| | - Patric J Jansson
- Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, New South Wales 2006, Australia.
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Conti S, Vexler A, Edry-Botzer L, Kalich-Philosoph L, Corn BW, Shtraus N, Meir Y, Hagoel L, Shtabsky A, Marmor S, Earon G, Lev-Ari S. Combined acetyl-11-keto-β-boswellic acid and radiation treatment inhibited glioblastoma tumor cells. PLoS One 2018; 13:e0198627. [PMID: 29969452 PMCID: PMC6029770 DOI: 10.1371/journal.pone.0198627] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/22/2018] [Indexed: 12/18/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-ĸB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-β-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-ĸB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin-fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-ĸB-inhibitor IĸB-α. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IĸB-α staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients.
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Affiliation(s)
- Sefora Conti
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Akiva Vexler
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Liat Edry-Botzer
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lital Kalich-Philosoph
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Benjamin W. Corn
- Institute of Radiotherapy, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Natan Shtraus
- Institute of Radiotherapy, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yaron Meir
- Institute of Radiotherapy, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lior Hagoel
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Alexander Shtabsky
- Pathology Department, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sylvia Marmor
- Pathology Department, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Gideon Earon
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shahar Lev-Ari
- Laboratory of Herbal Medicine and Cancer Research, Institute of Oncology, Tel-Aviv Medical Center affiliated to the Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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10
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Berger S, Procko E, Margineantu D, Lee EF, Shen BW, Zelter A, Silva DA, Chawla K, Herold MJ, Garnier JM, Johnson R, MacCoss MJ, Lessene G, Davis TN, Stayton PS, Stoddard BL, Fairlie WD, Hockenbery DM, Baker D. Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer. eLife 2016; 5. [PMID: 27805565 PMCID: PMC5127641 DOI: 10.7554/elife.20352] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 11/01/2016] [Indexed: 01/07/2023] Open
Abstract
Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.
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Affiliation(s)
- Stephanie Berger
- Department of Bioengineering, University of Washington, Seattle, United States
| | - Erik Procko
- Department of Biochemistry, University of Washington, Seattle, United States.,Department of Biochemistry, University of Illinois, Urbana, United States
| | - Daciana Margineantu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States.,Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Erinna F Lee
- Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia.,Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Betty W Shen
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Alex Zelter
- Department of Biochemistry, University of Washington, Seattle, United States
| | - Daniel-Adriano Silva
- Department of Biochemistry, University of Washington, Seattle, United States.,Institute for Protein Design, University of Washington, Seattle, United States
| | - Kusum Chawla
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States.,Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - Marco J Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Jean-Marc Garnier
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Richard Johnson
- Department of Genome Sciences, University of Washington, Seattle, United States
| | - Michael J MacCoss
- Department of Genome Sciences, University of Washington, Seattle, United States
| | - Guillaume Lessene
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia
| | - Trisha N Davis
- Department of Biochemistry, University of Washington, Seattle, United States
| | - Patrick S Stayton
- Department of Bioengineering, University of Washington, Seattle, United States
| | - Barry L Stoddard
- Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - W Douglas Fairlie
- Department of Chemistry and Physics, LaTrobe Institute for Molecular Science, Melbourne, Australia.,Olivia Newton-John Cancer Research Institute, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Australia.,School of Cancer Medicine, La Trobe University, Melbourne, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - David M Hockenbery
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, United States.,Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States
| | - David Baker
- Department of Biochemistry, University of Washington, Seattle, United States.,Institute for Protein Design, University of Washington, Seattle, United States.,Howard Hughes Medical Institute, University of Washington, Seattle, United States
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11
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Qi X, Xu W, Xie J, Wang Y, Han S, Wei Z, Ni Y, Dong Y, Han W. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis. Sci Rep 2016; 6:35788. [PMID: 27762347 PMCID: PMC5071902 DOI: 10.1038/srep35788] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 10/05/2016] [Indexed: 12/31/2022] Open
Abstract
Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.
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Affiliation(s)
- Xiaofeng Qi
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Wenguang Xu
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Junqi Xie
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Yufeng Wang
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Shengwei Han
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Zheng Wei
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China
| | - Yanhong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R China
| | - Yingchun Dong
- Department of Anesthesia, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R China
| | - Wei Han
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, No 30 Zhongyang Road, Nanjing, China.,Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, P.R China
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12
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Persaud SD, Park SW, Ishigami-Yuasa M, Koyano-Nakagawa N, Kagechika H, Wei LN. All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation. Sci Rep 2016; 6:22396. [PMID: 26935534 PMCID: PMC4776112 DOI: 10.1038/srep22396] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/11/2016] [Indexed: 12/16/2022] Open
Abstract
All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re-expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non-genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA’s toxicity caused by its genomic effects.
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Affiliation(s)
- Shawna D Persaud
- Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA
| | - Sung Wook Park
- Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA
| | - Mari Ishigami-Yuasa
- Tokyo Medical and Dental University (TMDU), Institute of Biomaterials and Bioengineering, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JAPAN
| | | | - Hiroyuki Kagechika
- Tokyo Medical and Dental University (TMDU), Institute of Biomaterials and Bioengineering, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, JAPAN
| | - Li-Na Wei
- Department of Pharmacology University of Minnesota, Minneapolis, MN 55455, USA
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13
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Pandey MK, Prasad S, Tyagi AK, Deb L, Huang J, Karelia DN, Amin SG, Aggarwal BB. Targeting Cell Survival Proteins for Cancer Cell Death. Pharmaceuticals (Basel) 2016; 9:11. [PMID: 26927133 PMCID: PMC4812375 DOI: 10.3390/ph9010011; 10.3390/biomedicines5020030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Escaping from cell death is one of the adaptations that enable cancer cells to stave off anticancer therapies. The key players in avoiding apoptosis are collectively known as survival proteins. Survival proteins comprise the Bcl-2, inhibitor of apoptosis (IAP), and heat shock protein (HSP) families. The aberrant expression of these proteins is associated with a range of biological activities that promote cancer cell survival, proliferation, and resistance to therapy. Several therapeutic strategies that target survival proteins are based on mimicking BH3 domains or the IAP-binding motif or competing with ATP for the Hsp90 ATP-binding pocket. Alternative strategies, including use of nutraceuticals, transcriptional repression, and antisense oligonucleotides, provide options to target survival proteins. This review focuses on the role of survival proteins in chemoresistance and current therapeutic strategies in preclinical or clinical trials that target survival protein signaling pathways. Recent approaches to target survival proteins-including nutraceuticals, small-molecule inhibitors, peptides, and Bcl-2-specific mimetic are explored. Therapeutic inventions targeting survival proteins are promising strategies to inhibit cancer cell survival and chemoresistance. However, complete eradication of resistance is a distant dream. For a successful clinical outcome, pretreatment with novel survival protein inhibitors alone or in combination with conventional therapies holds great promise.
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Affiliation(s)
- Manoj K Pandey
- Department of Pharmacology, College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA.
| | - Sahdeo Prasad
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Amit Kumar Tyagi
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Lokesh Deb
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Jiamin Huang
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Deepkamal N Karelia
- Department of Pharmacology, College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA.
| | - Shantu G Amin
- Department of Pharmacology, College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA.
| | - Bharat B Aggarwal
- Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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14
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Targeting Cell Survival Proteins for Cancer Cell Death. Pharmaceuticals (Basel) 2016; 9:ph9010011. [PMID: 26927133 PMCID: PMC4812375 DOI: 10.3390/ph9010011] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 02/08/2016] [Accepted: 02/16/2016] [Indexed: 12/18/2022] Open
Abstract
Escaping from cell death is one of the adaptations that enable cancer cells to stave off anticancer therapies. The key players in avoiding apoptosis are collectively known as survival proteins. Survival proteins comprise the Bcl-2, inhibitor of apoptosis (IAP), and heat shock protein (HSP) families. The aberrant expression of these proteins is associated with a range of biological activities that promote cancer cell survival, proliferation, and resistance to therapy. Several therapeutic strategies that target survival proteins are based on mimicking BH3 domains or the IAP-binding motif or competing with ATP for the Hsp90 ATP-binding pocket. Alternative strategies, including use of nutraceuticals, transcriptional repression, and antisense oligonucleotides, provide options to target survival proteins. This review focuses on the role of survival proteins in chemoresistance and current therapeutic strategies in preclinical or clinical trials that target survival protein signaling pathways. Recent approaches to target survival proteins-including nutraceuticals, small-molecule inhibitors, peptides, and Bcl-2-specific mimetic are explored. Therapeutic inventions targeting survival proteins are promising strategies to inhibit cancer cell survival and chemoresistance. However, complete eradication of resistance is a distant dream. For a successful clinical outcome, pretreatment with novel survival protein inhibitors alone or in combination with conventional therapies holds great promise.
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15
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Cui Y, Lin J, Zuo J, Zhang L, Dong Y, Hu G, Luo C, Chen J, Lu Y. AKT2-knockdown suppressed viability with enhanced apoptosis, and attenuated chemoresistance to temozolomide of human glioblastoma cells in vitro and in vivo. Onco Targets Ther 2015; 8:1681-90. [PMID: 26185456 PMCID: PMC4501163 DOI: 10.2147/ott.s83795] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The AKT2 kinase (protein kinase Bβ) is overexpressed in high-grade gliomas. Upregulation of the AKT2 gene has been previously observed in glioblastoma patients suffering from chemotherapy failure and tumor progress. In this study, we aimed to evaluate the effect of AKT2 on viability and chemoresistance in the human glioblastoma cell line U251. The U251 cell line was stably transfected with short hairpin RNA (shRNA) targeting AKT2. U251 cells underexpressing AKT2 were then examined for viability with temozolomide (TMZ) treatment, and tested for cell apoptosis both in vitro and in tumor-implanted mice. Next, expressions of several chemoresistance-related molecules were measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blot analysis. The results showed that the 50% inhibitory concentration (IC50) of AKT2 shRNA-transfected cells was significantly lower compared with Lenti-GFP-transfected and nontransfected controls and that the tumor growth of the AKT2-shRNA and TMZ combined-treated mice was obviously suppressed in either mass or volume. Concomitantly, the apoptosis of TMZ-treated tumor cells was significantly enhanced after knockdown of AKT2, as measured by flow cytometry and in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Furthermore, AKT2-inhibition in TMZ-treated glioblastoma U251 cells upregulated apoptotic effector caspase-3, whereas it downregulated antiapoptotic protein Bcl-2, DNA repairing protein MGMT, and drug efflux pump protein MRP1. Our study identified AKT2 as an important gene in presenting chemoresistance in glioblastoma, and a potential target to potentiate the clinical effect of chemotherapy in glioma treatment.
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Affiliation(s)
- Yong Cui
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jing Lin
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Jianling Zuo
- Department of Neurosurgery, First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
| | - Lei Zhang
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yan Dong
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Guohan Hu
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Chun Luo
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Juxiang Chen
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Yicheng Lu
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China
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16
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Akkoç Y, Berrak Ö, Arısan ED, Obakan P, Çoker-Gürkan A, Palavan-Ünsal N. Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells. Biomed Pharmacother 2015; 71:161-71. [PMID: 25960232 DOI: 10.1016/j.biopha.2015.02.029] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 02/21/2015] [Indexed: 01/16/2023] Open
Abstract
Curcumin is a natural anti-cancer agent derived from turmeric (Curcuma longa). Curcumin triggers intrinsic apoptotic cell death by activating mitochondrial permeabilization due to the altered expression of pro- and anti-apoptotic Bcl-2 family members. Phosphoinositol-3-kinase (PI3K) and Akt, key molecular players in the survival mechanism, have been shown to be associated with the Bcl-2 signaling cascade; therefore, evaluating the therapeutic efficiency of drugs that target both survival and the apoptosis mechanism has gained importance in cancer therapy. We found that Bcl-2 overexpression is a limiting factor for curcumin-induced apoptosis in highly metastatic MCF-7 breast cancer cells. Forced overexpression of Bcl-2 also blocked curcumin-induced autophagy in MCF-7 cells, through its inhibitory interactions with Beclin-1. Pre-treatment of PI3K inhibitor LY294002 enhanced curcumin-induced cell death, apoptosis, and autophagy via modulating the expression of Bcl-2 family members and autophagosome formation in MCF-7 breast cancer cells. Atg7 silencing further increased apoptotic potential of curcumin in the presence or absence of LY294002 in wt and Bcl-2+ MCF-7 cells. The findings of this study support the hypothesis that blocking the PI3K/Akt pathway may further increased curcumin-induced apoptosis and overcome forced Bcl-2 expression level mediated autophagic responses against curcumin treatment in MCF-7 cells.
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Affiliation(s)
- Yunus Akkoç
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey
| | - Özge Berrak
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey
| | - Elif Damla Arısan
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
| | - Pınar Obakan
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey
| | - Ajda Çoker-Gürkan
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey
| | - Narçin Palavan-Ünsal
- Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey
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17
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Nicholson AD, Guo X, Sullivan CA, Cha CH. Automated Quantitative Analysis of Tissue Microarray of 443 Patients with Colorectal Adenocarcinoma: Low Expression of Bcl-2 Predicts Poor Survival. J Am Coll Surg 2014; 219:977-87. [DOI: 10.1016/j.jamcollsurg.2014.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 07/07/2014] [Accepted: 07/10/2014] [Indexed: 10/25/2022]
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18
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Anuf AR, Ramachandran R, Krishnasamy R, Gandhi PSS, Periyasamy S. Antiproliferative effects of Plumbago rosea and its purified constituent plumbagin on SK-MEL 28 melanoma cell lines. Pharmacognosy Res 2014; 6:312-9. [PMID: 25276069 PMCID: PMC4166820 DOI: 10.4103/0974-8490.138280] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 05/20/2014] [Accepted: 08/06/2014] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Plumbago rosea is used in traditional systems of medicine for the preparation of formulations used for treating inflammations, cough, bronchitis, and gastrointestinal disorders, and also in conjunction with cancer chemotherapy. In the present study, the cytotoxic and anti-proliferative effects of plumbagin, and the ethanolic root extract of P. rosea (ETPR) was evaluated on SK-MEL 28 melanoma cell lines and human lymphocytes. MATERIALS AND METHODS MTT and apoptotic assays were used for the evaluation of cytotoxic and anti-proliferative effects, respectively. In addition, the effect of Plumbagin and ETPR in down regulation of BCL-2 expression is investigated using RT-PCR analysis. RESULTS Both plumbagin and ETPR dose-dependently decreased the cell viability more potently in melanoma cell lines. P. rosea extract demonstrated significant synergy in inhibiting BCL-2 expression than plumbagin. Moreover plumbagin showed more toxicity in human lymphocytes. CONCLUSION Plumbagin has anti-cancer potential, but the side effects limits its use; yet plumbagin, in combination with other ingredients in Plumbago rosea extract, displays significant synergy leading to a stronger anticancer effect with significantly less toxicity.
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Affiliation(s)
- Alexander Ronaldo Anuf
- Department of Biotechnology, Kamaraj College of Engineering and Technology, Virudhunagar,Tamil Nadu, India
| | | | - Rajaram Krishnasamy
- Department of Biotechnology, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, Tamil Nadu, India
| | - P S Sudhakar Gandhi
- Department of Biotechnology, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, Tamil Nadu, India
| | - Sureshkumar Periyasamy
- Department of Biotechnology, Bharathidasan Institute of Technology Campus, Anna University, Tiruchirappalli, Tamil Nadu, India
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19
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Xiao Q, Hu Y, Liu Y, Wang Z, Geng H, Hu L, Xu D, Wang K, Zheng L, Zheng S, Ding K. BEX1 promotes imatinib-induced apoptosis by binding to and antagonizing BCL-2. PLoS One 2014; 9:e91782. [PMID: 24626299 PMCID: PMC3953594 DOI: 10.1371/journal.pone.0091782] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 02/14/2014] [Indexed: 12/21/2022] Open
Abstract
An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.
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Affiliation(s)
- Qian Xiao
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yeting Hu
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yue Liu
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhanhuai Wang
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haitao Geng
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lifeng Hu
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dengyong Xu
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ke Wang
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lei Zheng
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Oncology and Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- * E-mail: (KD); (SZ); (LZ)
| | - Shu Zheng
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- * E-mail: (KD); (SZ); (LZ)
| | - Kefeng Ding
- The Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, The Key Laboratory of Molecular Biology in Medical Sciences of Zhejiang Province, Cancer Institute, Hangzhou, Zhejiang, China
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- * E-mail: (KD); (SZ); (LZ)
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Hung N, Chen YJ, Taha A, Olivecrona M, Boet R, Wiles A, Warr T, Shaw A, Eiholzer R, Baguley BC, Eccles MR, Braithwaite AW, Macfarlane M, Royds JA, Slatter T. Increased paired box transcription factor 8 has a survival function in glioma. BMC Cancer 2014; 14:159. [PMID: 24602166 PMCID: PMC4015841 DOI: 10.1186/1471-2407-14-159] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 02/28/2014] [Indexed: 11/10/2022] Open
Abstract
Background The molecular basis to overcome therapeutic resistance to treat glioblastoma remains unclear. The anti-apoptotic b cell lymphoma 2 (BCL2) gene is associated with treatment resistance, and is transactivated by the paired box transcription factor 8 (PAX8). In earlier studies, we demonstrated that increased PAX8 expression in glioma cell lines was associated with the expression of telomerase. In this current study, we more extensively explored a role for PAX8 in gliomagenesis. Methods PAX8 expression was measured in 156 gliomas including telomerase-negative tumours, those with the alternative lengthening of telomeres (ALT) mechanism or with a non-defined telomere maintenance mechanism (NDTMM), using immunohistochemistry and quantitative PCR. We also tested the affect of PAX8 knockdown using siRNA in cell lines on cell survival and BCL2 expression. Results Seventy-two percent of glioblastomas were PAX8-positive (80% telomerase, 73% NDTMM, and 44% ALT). The majority of the low-grade gliomas and normal brain cells were PAX8-negative. The suppression of PAX8 was associated with a reduction in both cell growth and BCL2, suggesting that a reduction in PAX8 expression would sensitise tumours to cell death. Conclusions PAX8 is increased in the majority of glioblastomas and promoted cell survival. Because PAX8 is absent in normal brain tissue, it may be a promising therapeutic target pathway for treating aggressive gliomas.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Tania Slatter
- Department of Pathology, University of Otago, Dunedin, New Zealand.
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Li W, Qian C, Wang L, Teng H, Zhang L. Association of BCL2-938C>A genetic polymorphism with glioma risk in Chinese Han population. Tumour Biol 2013; 35:2259-64. [DOI: 10.1007/s13277-013-1299-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 10/07/2013] [Indexed: 01/12/2023] Open
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22
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Alexander BM, Ligon KL, Wen PY. Enhancing radiation therapy for patients with glioblastoma. Expert Rev Anticancer Ther 2013; 13:569-81. [PMID: 23617348 DOI: 10.1586/era.13.44] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Radiation therapy has been the foundation of therapy following maximal surgical resection in patients with newly diagnosed glioblastoma for decades and the primary therapy for unresected tumors. Using the standard approach with radiation and temozolomide, however, outcomes are poor, and glioblastoma remains an incurable disease with the majority of recurrences and progression within the radiation treatment field. As such, there is much interest in elucidating the mechanisms of resistance to radiation therapy and in developing novel approaches to overcoming this treatment resistance.
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Affiliation(s)
- Brian M Alexander
- Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, 75 Francis Street, ASB1-L2, Boston, MA 02115, USA.
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Steele A, Uckan D, Chamizo W, Ferre P, Thomas B, Edwards T, Steele P, Koutsonikolis A, Good RA. An Optimized Immunohistochemical Protocol for Both Manual and Automated Staining of Formalin Fixed, Paraffin Embedded Human Placenta for Demonstration and Analyses of FAS, FAS-L, and Bcl-2. J Histotechnol 2013. [DOI: 10.1179/his.1998.21.4.285] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Vinod BS, Maliekal TT, Anto RJ. Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance. Antioxid Redox Signal 2013; 18:1307-48. [PMID: 22871022 DOI: 10.1089/ars.2012.4573] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.
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Affiliation(s)
- Balachandran S Vinod
- Cancer Research Program, Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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25
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Liu B, Chen Q, Tian D, Wu L, Dong H, Wang J, Ji B, Zhu X, Cai Q, Wang L, Zhang S. BMP4 reverses multidrug resistance through modulation of BCL-2 and GDNF in glioblastoma. Brain Res 2013; 1507:115-24. [PMID: 23466456 DOI: 10.1016/j.brainres.2013.02.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 01/16/2013] [Accepted: 02/19/2013] [Indexed: 01/15/2023]
Abstract
Patients with glioblastoma are commonly treated with chemotherapy. But a significant proportion of patients develop disease progression after an initial response to chemotherapy. Presently, there is no standard of care for such patients. The bone morphogenetic protein 4 (BMP4) has been reported to play a tumor-suppressing role in glioblastoma, but its role in glioblastoma multidrug resistance (MDR) is not clear. We reported that BMP4 can reverse MDR of glioblastoma through the inhibition of B-cell lymphoma 2(BCL-2) and glial cell derived neurotrophic factor (GDNF). We showed that the expression level of BMP4 was lower in glioblastoma compared to normal brain tissue, and also showed that BMP4 expression decreased in multidrug resistance cell line U251/TMZ compared to U251 cells. Our research demonstrated that over-expression of BMP4 can reverse the multidrug resistance. BCL-2 and GDNF were inhibited when BMP4 was over-expressed, and this data were consistent with the negative relationship in human samples; analysis of 40 patient's glioblastoma and brain samples revealed a significant negative correlation between BMP4 and BCL-2, GDNF. When BCL-2 and GDNF were knocked down, the effect of BMP4 in regulating MDR was partially lost. This novel result showed, for the first time, that BMP4 can reverse MDR in glioblastoma, which involved negative inhibition of BCL-2 and GDNF.
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Affiliation(s)
- Baohui Liu
- Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan 430060, Hubei, China
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Thomas S, Quinn BA, Das SK, Dash R, Emdad L, Dasgupta S, Wang XY, Dent P, Reed JC, Pellecchia M, Sarkar D, Fisher PB. Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets 2012; 17:61-75. [PMID: 23173842 DOI: 10.1517/14728222.2013.733001] [Citation(s) in RCA: 200] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation. AREAS COVERED This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 family proteins, recent approaches use small molecule inhibitors (SMIs) and peptides. Structural similarity of the Bcl-2 family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics. EXPERT OPINION Strategies to specifically identify and inhibit critical determinants that promote therapy resistance and tumor progression represent viable approaches for developing effective cancer therapies. From a clinical perspective, pretreatment with novel, potent Bcl-2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. Identifying SMIs with broader and higher affinities for inhibiting all of the Bcl-2 pro-survival proteins will facilitate development of superior cancer therapies.
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Affiliation(s)
- Shibu Thomas
- Virginia Commonwealth University, Department of Human and Molecular Genetics, Richmond, VA 23298, USA
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Vogelbaum MA, Tong JX, Higashikubo R, Gutmann DH, Rich KM. Transfection of C6 glioma cells with the bax gene and increased sensitivity to treatment with cytosine arabinoside. Neurosurg Focus 2012; 3:Article3. [PMID: 17206779 DOI: 10.3171/foc.1997.3.5.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Genes known to be involved in the regulation of apoptosis include members of the bcl-2 gene family, such as inhibitors of apoptosis (bcl-2 and bcl-xl) and promotors of apoptosis (bax). The authors investigated a potential approach for the treatment of malignant gliomas by using a gene transfection technique to manipulate the level of an intracellular protein involved in the control of apoptosis. The authors transfected the murine bax gene, which had been cloned into a mammalian expression vector, into the C6 rat glioma cell line. Overexpression of the bax gene resulted in a decreased growth rate (average doubling time of 32.96 hours compared with 22.49 hours for untransfected C6, and 23.11 hours for clones transfected with pcDNA3 only), which may be caused, in part, by an increased rate of spontaneous apoptosis (0.77 +/- 0.15% compared with 0.42 +/- 0.08% for the vector-only transfected C6 cell line; p = 0.038, two-tailed Student's t-test). Treatment with 1 microM of cytosine arabinoside (ara-C) resulted in significantly more cells undergoing apoptosis in the cell line overexpressing bax than in the vector-only control cell line (23.57 +/- 2.6% compared with 5.3 +/- 0.7% terminal deoxynucleotidyl transferase--mediated biotinylated--deoxyuridine triphosphate nick-end labeling technique-positive cells; p = 0.007). Furthermore, measurements of growth curves obtained immediately after treatment with 0.5 microM ara-C demonstrated a prolonged growth arrest of at least 6 days in the cell line overexpressing bax. These results can be used collectively to argue that overexpression of bax results in increased sensitivity of C6 cells to ara-C and that increasing bax expression may be a useful strategy, in general, for increasing the sensitivity of gliomas to antineoplastic treatments.
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Affiliation(s)
- M A Vogelbaum
- Department of Neurological Surgery and Neurology, and Department of Radiology, Washington University School of Medicine, St. Louis, Missouri
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Ma R, Zhang G, Wang H, Lv H, Fang F, Kang X. Downregulation of miR-544 in tissue, but not in serum, is a novel biomarker of malignant transformation in glioma. Oncol Lett 2012. [PMID: 23205130 DOI: 10.3892/ol.2012.918] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Low-grade glioma is predisposed to progress to anaplastic astrocytoma and eventually secondary glioblastoma. The malignant transformation may involve the accumulation of multiple genetic alterations. The purpose of this study was to explore the role of miR-544 in glioma progression and discuss whether it may be a novel biomarker of malignant transformation. The expression of miR-544 was measured in a series of 198 glioma samples (63 low-grade glioma, 44 anaplastic astrocytoma and 91 glioblastoma tumors) using microarrays. Quantitative real-time reverse transcription PCR (qRT-PCR) was used to validate the expression levels of miR-544 in tissue and serum samples in an independent validated cohort (25 low-grade glioma, 21 anaplastic astrocytoma and 20 glioblastoma tumors). A Pearson correlation analysis was performed to examine the correlation between miR-544 levels of tissue and serum samples. Microarrays revealed that the expression levels of miR-544 decreased significantly in anaplastic gliomas (P<0.01) or glioblastoma (P<0.01) compared with low-grade gliomas. In an independent cohort of glioma patients, miR-544 exhibited a progression-associated downregulation in glioma tumors. The levels of miR-544 in serum samples tended to be lower in anaplastic and glioblastoma patients compared with low-grade gliomas, but with no significant difference. The Pearson correlation analysis revealed a weakly positive correlation between tissue and serum levels of miR-544. These data support a significant role for miR-544 aberration in the malignant transformation of glioma. The downregulation of miR-544 in tissue may be used as a novel biomarker.
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Affiliation(s)
- Ruimin Ma
- Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University, Dongcheng, Beijing 100050
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Hu BS, Tan JW, Zhu GH, Wang DF, Zhou X, Sun ZQ. WWOX induces apoptosis and inhibits proliferation of human hepatoma cell line SMMC-7721. World J Gastroenterol 2012; 18:3020-6. [PMID: 22736928 PMCID: PMC3380332 DOI: 10.3748/wjg.v18.i23.3020] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/28/2011] [Accepted: 01/07/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of the WWOX gene on the human hepatic carcinoma cell line SMMC-7721.
METHODS: Full-length WWOX cDNA was amplified from normal human liver tissues. Full-length cDNA was subcloned into pEGFP-N1, a eukaryotic expression vector. After introduction of the WWOX gene into cancer cells using liposomes, the WWOX protein level in the cells was detected through Western blotting. Cell growth rates were assessed by methyl thiazolyl tetrazolium (MTT) and colony formation assays. Cell cycle progression and cell apoptosis were measured by flow cytometry. The phosphorylated protein kinase B (AKT) and activated fragments of caspase-9 and caspase-3 were examined by Western blotting analysis.
RESULTS: WWOX significantly inhibited cell proliferation, as evaluated by the MTT and colony formation assays. Cells transfected with WWOX showed significantly higher apoptosis ratios when compared with cells transfected with a mock plasmid, and overexpression of WWOX delayed cell cycle progression from G1 to S phase, as measured by flow cytometry. An increase in apoptosis was also indicated by a remarkable activation of caspase-9 and caspase-3 and a dephosphorylation of AKT (Thr308 and Ser473) measured with Western blotting analysis.
CONCLUSION: Overexpression of WWOX induces apoptosis and inhibits proliferation of the human hepatic carcinoma cell line SMMC-7721.
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Xiao YH, Li XH, Tan T, Liang T, Yi H, Li MY, Zeng GQ, Wan XX, Qu JQ, He QY, Li JH, Chen Y, Xiao ZQ. Identification of GLIPR1 tumor suppressor as methylation-silenced gene in acute myeloid leukemia by microarray analysis. J Cancer Res Clin Oncol 2011; 137:1831-40. [PMID: 21922325 DOI: 10.1007/s00432-011-1065-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2011] [Accepted: 09/02/2011] [Indexed: 12/31/2022]
Abstract
PURPOSE To identify methylation-silenced genes in acute myeloid leukemia (AML). METHODS Microarray analyses were performed in AML cell line HL-60 cells exposed to the demethylating agent 5-aza-2dC. The methylation status and expression of glioma pathogenesis-related protein 1 (GLIPR1), one of highly induced genes by demethylation, were further detected in six hematopoietic malignancy cell lines and 260 bone marrow samples from leukemia patients and nonmalignant diseases as control, as well as pre-treated and post-treated bone marrow samples from 24 complete remission AML patients received chemotherapy using MS-PCR, bisulfite DNA sequencing, RT-PCR, and Western blotting. RESULTS One hundred and nine genes were significantly induced by demethylation in HL-60 cells, 12 genes of which were confirmed by RT-PCR. GLIPR1, a tumor suppressor gene, was frequently methylation-silenced in AML cell lines and AML patients, but not in the other hematopoietic malignancy cell lines and patients. The frequencies of methylation-silenced GLIPR1 in the pre-treatment were significantly higher than those in the post-treatment in complete remission AML patients. CONCLUSION We identify 109 genes induced by demethylation in HL-60 cells, and demonstrate that GLIPR1 is a methylation-silenced gene in the AML patients, and may serve as a marker for monitoring disease activity during therapy in the AML patients. The data provide the important information for studying the pathogenesis of AML and discovering the target genes of methylating agents.
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Affiliation(s)
- Yan-Hua Xiao
- Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
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Doucette T, Yang Y, Zhang W, Fuller GN, Suki D, Fults DW, Rao G. Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma. Int J Cancer 2011; 129:2093-103. [PMID: 21171016 PMCID: PMC3196817 DOI: 10.1002/ijc.25869] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2010] [Revised: 11/22/2010] [Accepted: 11/30/2010] [Indexed: 01/25/2023]
Abstract
A significant subset of gliomas arises after activation of the proproliferative platelet-derived growth factor (PDGF) pathway. The progression of low-grade gliomas to more malignant tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Antiapoptotic genes are overexpressed in a variety of cancers, and the antiapoptotic gene, BCL2, is associated with treatment resistance and tumor recurrence in gliomas. However, the impact of antiapoptotic gene expression to tumor formation and progression is unclear. We overexpressed Bcl-2 in a PDGFB-dependent mouse model of oligodendroglioma, a common glioma subtype, to assess its effect in vivo. We hypothesized that the antiapoptotic effect would complement the proproliferative effect of PDGFB to promote tumor formation and progression to anaplastic oligodendroglioma (AO). Here, we show that coexpression of PDGFB and Bcl-2 results in a higher overall tumor formation rate compared to PDGFB alone. Coexpression of PDGFB and Bcl-2 promotes progression to AO with prominent foci of necrosis, a feature of high-grade gliomas. Median tumor latency was shorter in mice injected with PDGFB and Bcl-2 compared to those injected with PDGFB alone. Although independent expression of Bcl-2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase-3 expression) was more pronounced in AOs induced by PDGFB and Bcl-2 compared to those induced by PDGFB alone. Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high-grade tumors induced by PDGFB and Bcl-2. Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype.
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Affiliation(s)
- Tiffany Doucette
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Dizaji MZ, Malehmir M, Ghavamzadeh A, Alimoghaddam K, Ghaffari SH. Synergistic Effects of Arsenic Trioxide and Silibinin on Apoptosis and Invasion in Human Glioblastoma U87MG Cell Line. Neurochem Res 2011; 37:370-80. [DOI: 10.1007/s11064-011-0620-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 08/27/2011] [Accepted: 09/23/2011] [Indexed: 01/08/2023]
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Nieto-Sampedro M, Valle-Argos B, Gómez-Nicola D, Fernández-Mayoralas A, Nieto-Díaz M. Inhibitors of Glioma Growth that Reveal the Tumour to the Immune System. Clin Med Insights Oncol 2011; 5:265-314. [PMID: 22084619 PMCID: PMC3201112 DOI: 10.4137/cmo.s7685] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 μM or higher.At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.
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Affiliation(s)
- Manuel Nieto-Sampedro
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Beatriz Valle-Argos
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
| | - Diego Gómez-Nicola
- Instituto Cajal de Neurobiología, CSIC, 28002 Madrid, Spain
- Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain
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Abstract
Gliobastoma multiform (GBM) is the most common and aggressive brain tumor, which is characterized by its infiltrative nature. Current standard therapy for GBMs consists of surgery followed by radiotherapy combined with the alkylating agent temozolomide (TMZ). Recent clinical trials have demonstrated that this chemo-irradiation approach results in a significant increase in survival compared to radiotherapy alone. Nevertheless, due to tumor recurrence, the median survival time is still limited to approximately 15 months. Recently, several studies have focused on aberrant signal transduction in GBM, resistance mechanisms of GBM to TMZ and to radiotherapy. Attention has been focused on molecular targets including phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, protein kinase C (pKC) pathway, Ras/mitogen-activated protein kinase pathway (MAPK), Wnt pathway and intrinsic or extrinsic apoptosis pathways. In addition, research has been directed to radiotherapy and radiosensitizing agents, and cancer gene therapy as well. This article will address several resistance mechanisms of GBM to chemotherapy and radiotherapy and the recent preclinical and clinical studies on targeted therapy.
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Affiliation(s)
- N H Rekers
- Department of Medical Oncology, VU University Medical Center, The Netherlands
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Debien E, Hervouet E, Gautier F, Juin P, Vallette FM, Cartron PF. ABT-737 and/or folate reverse the PDGF-induced alterations in the mitochondrial apoptotic pathway in low-grade glioma patients. Clin Epigenetics 2011; 2:369-381. [PMID: 21949549 PMCID: PMC3156333 DOI: 10.1007/s13148-011-0035-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Accepted: 04/10/2011] [Indexed: 10/27/2022] Open
Abstract
Elevated activation of the platelet-derived growth factor (PDGF) pathway, apoptosis evasion phenotype, and global DNA hypomethylation are hallmarks frequently observed in cancers, such as in low-grade glioma (LGG). However, the orchestration of these malignant functions is not fully elucidated in LGG. Our study reveals that the co-presence of these hallmarks in the same LGG is frequent and confers poor prognosis in patients with LGG. Our data also indicate that the apoptosis evasion phenotype of these cells harboring a hypomethylation-induced activation of the PDGF pathway is associated with a hypomethylation of the bcl-xl and bcl-w genes and the phosphorylation and/or downregulation of three major pro-apoptotic BH3-only proteins: PUMA, Bad, and Bim. Consistent with this, we demonstrate that the use of folate, a DNA-methylating agent, promotes the reprogramming of the sensitivity of glioma cells to ABT-737/etoposide-induced apoptosis and reduces the dose of ABT-737 required to promote etoposide-induced apoptosis. This work supports the idea that the inclusion of folate and/or ABT-737 could be a promising adjuvant in the design of anti-glioma therapeutic protocols in clinical studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13148-011-0035-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Emilie Debien
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 quai moncousu, BP7021, 44007 Nantes, France
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
| | - Eric Hervouet
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 quai moncousu, BP7021, 44007 Nantes, France
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
| | - Fabien Gautier
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Survie cellulaire et échappement tumoral dans les cancers du sein, 8 quai moncousu, BP7021, 44007 Nantes, France
- Département de Biologie Oncologique, ICO René Gauducheau, Bd J. Monod, 44805 Nantes-Saint Herblain, France
| | - Philippe Juin
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Survie cellulaire et échappement tumoral dans les cancers du sein, 8 quai moncousu, BP7021, 44007 Nantes, France
| | - Francois M. Vallette
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 quai moncousu, BP7021, 44007 Nantes, France
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
| | - Pierre-Francois Cartron
- Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe Apoptose et Progression Tumorale, 8 quai moncousu, BP7021, 44007 Nantes, France
- Faculté de Médecine, Département de Recherche en Cancérologie, IFR26, Université de Nantes, 4400 Nantes, France
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Lepiller Q, Aziz Khan K, Di Martino V, Herbein G. Cytomegalovirus and tumors: two players for one goal-immune escape. Open Virol J 2011; 5:60-9. [PMID: 21760870 PMCID: PMC3134960 DOI: 10.2174/1874357901105010060] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Revised: 04/10/2011] [Accepted: 04/12/2011] [Indexed: 12/22/2022] Open
Abstract
Cytomegalovirus (CMV) and the human tumor cell share the same objectives: escape the recognition and destruction by the immune system and establish a state of immune tolerance conducive for their development. For early tumor development, the escape of the first lines of defense of the immune surveillance is a critical step which determines survival or destruction. The presence of CMV on the tumor site and its involvement in carcinogenesis as initiator or promoter is increasingly documented. In this article, we highlight the similarity between mechanisms used by tumors and CMV to circumvent the immune defenses and evade from immune surveillance. We suggest that CMV and tumors help one another for their common objective. CMV gets shelter in immunologically poor environment of the tumor cells. In return CMV, by acting directly on the cancer cell and/or on the tumor microenvironment, provides the tumor cell the ways to promote its immune escape and development of immune tolerance.
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Affiliation(s)
- Quentin Lepiller
- Department of Virology, University of Franche-Comte, UPRES EA 4266, IFR 133, CHU Besancon, F-25030 Besanon, France
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El Hindy N, Bachmann HS, Lambertz N, Adamzik M, Nückel H, Worm K, Zhu Y, Sure U, Siffert W, Sandalcioglu IE. Association of the CC genotype of the regulatory BCL2 promoter polymorphism (-938C>A) with better 2-year survival in patients with glioblastoma multiforme. J Neurosurg 2011; 114:1631-9. [PMID: 21250804 DOI: 10.3171/2010.12.jns10478] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECT Bcl-2 plays a key role in the downregulation of apoptosis and proliferation and leads to increased chemoresistance in glioblastoma multiforme (GBM). The authors investigated the role of a common regulatory single-nucleotide polymorphism (-938C>A), which is located in the inhibitory P2 promoter of BCL2. METHODS Data from 160 patients suffering from GBM were retrospectively evaluated. Study inclusion criteria consisted of available DNA and, in patients still alive, a follow-up of at least 24 months. Results were analyzed with respect to the basic clinical data, type of surgical intervention (gross-total resection [GTR] versus stereotactic biopsy [SB]), adjuvant therapy, MGMT promoter methylation, and survival at the 2-year follow-up. RESULTS At the 2-year follow-up, 127 (79.4%) of the 160 patients had died. Kaplan-Meier curves revealed a significantly higher rate of survival for homo- and heterozygous C-allele carriers (p = 0.031). In the GTR group, the survival rate was 47.1% for homozygous C-allele carriers, 32.0% for heterozygous C-allele carriers, and only 21.4% for homozygous A-allele carriers (p = 0.024). The SB group showed no genotype-dependent differences. Multivariable Cox regression revealed that the BCL2 (-938AA) genotype was an independent negative prognostic factor for 2-year survival in the GTR group according to the BCL2 (-938CC) genotype reference group (hazard ratio 2.50, 95% CI 1.14-5.48, p = 0.022). CONCLUSIONS These results suggested that the (-938C>A) polymorphism is a survival prognosticator as well as a marker for a high-risk group among patients with GBM who underwent GTR.
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Affiliation(s)
- Nicolai El Hindy
- Department of Neurosurgery, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
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Kane AJ, Sughrue ME, Rutkowski MJ, Tihan T, Parsa AT. The molecular pathology of central neurocytomas. J Clin Neurosci 2011; 18:1-6. [DOI: 10.1016/j.jocn.2010.06.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2010] [Accepted: 06/09/2010] [Indexed: 11/29/2022]
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40
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Ordys BB, Launay S, Deighton RF, McCulloch J, Whittle IR. The role of mitochondria in glioma pathophysiology. Mol Neurobiol 2010; 42:64-75. [PMID: 20414816 DOI: 10.1007/s12035-010-8133-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2010] [Accepted: 04/05/2010] [Indexed: 10/19/2022]
Abstract
It has long been recognised that malignant tumours favour aerobic glycolysis to generate ATP and contain abnormalities of the intrinsic, mitochondria-dependent, apoptotic pathway, suggesting the involvement of dysfunctional mitochondria in tumour pathophysiology. However, the mechanisms underlying such processes in gliomas are poorly understood. Few recent studies have evaluated mitochondrial ultrastructure and proteomics in the pathophysiology of malignant gliomas. However, aberrant energy metabolism has been reported in gliomas and mitochondrial dysfunction links to glioma apoptotic signalling have been observed. Mitochondrial structural abnormalities and dysfunction in malignant gliomas is a neglected area of research. Definition of abnormalities in mitochondrial proteomics, membrane potential regulation, energy metabolism and intrinsic apoptotic pathway signalling in gliomas may open novel therapeutic opportunities.
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Affiliation(s)
- Bartlomiej B Ordys
- Department of Clinical Neurosciences, Western General Hospital, University of Edinburgh, Edinburgh EH42XU, UK
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41
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Molecular analysis of WWOX expression correlation with proliferation and apoptosis in glioblastoma multiforme. J Neurooncol 2010; 101:207-13. [PMID: 20535528 PMCID: PMC2996532 DOI: 10.1007/s11060-010-0254-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2009] [Accepted: 05/24/2010] [Indexed: 12/27/2022]
Abstract
Glioblastoma multiforme is the most common type of primary brain tumor in adults. WWOX is a tumor suppressor gene involved in carcinogenesis and cancer progression in many different neoplasms. Reduced WWOX expression is associated with more aggressive phenotype and poor patient outcome in several cancers. We investigated alternations of WWOX expression and its correlation with proliferation, apoptosis and signal trafficking in 67 glioblastoma multiforme specimens. Moreover, we examined the level of WWOX LOH and methylation status in WWOX promoter region. Our results suggest that loss of heterozygosity (relatively frequent in glioblastoma multiforme) along with promoter methylation may decrease the expression of this tumor suppressor gene. Our experiment revealed positive correlations between WWOX and Bcl2 and between WWOX and Ki67. We also confirmed that WWOX is positively correlated with ErbB4 signaling pathway in glioblastoma multiforme.
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Grzmil M, Hemmings BA. Deregulated signalling networks in human brain tumours. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2009; 1804:476-83. [PMID: 19879382 DOI: 10.1016/j.bbapap.2009.10.018] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Revised: 10/13/2009] [Accepted: 10/21/2009] [Indexed: 01/17/2023]
Abstract
Despite the variety of modern therapies against human brain cancer, in its most aggressive form of glioblastoma multiforme (GBM) it is a still deadly disease with a median survival of approximately 1 year. Over the past 2 decades, molecular profiling of low- and high-grade malignant brain tumours has led to the identification and molecular characterisation of mechanisms leading to brain cancer development, maintenance and progression. Genetic alterations occurring during gliomagenesis lead to uncontrolled tumour growth stimulated by deregulated signal transduction pathways. The characterisation of hyperactivated signalling pathways has identified many potential molecular targets for therapeutic interference in human gliomas. Overexpressed or mutated and constitutively active kinases are attractive targets for low-molecular-weight inhibitors. Although the first attempts with mono-therapy using a single targeted kinase inhibitor were not satisfactory, recent studies based on the simultaneous targeting of several core hyperactivated pathways show great promise for the development of novel therapeutic approaches. This review focuses on genetic alterations leading to the activation of key deregulated pathways in human gliomas.
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Affiliation(s)
- Michal Grzmil
- Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
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Moliterno JA, Henry E, Pannullo SC. Corticorelin acetate injections for the treatment of peritumoral brain edema. Expert Opin Investig Drugs 2009; 18:1413-9. [DOI: 10.1517/13543780903190689] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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44
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Snuderl M, Chi SN, De Santis SM, Stemmer-Rachamimov AO, Betensky RA, De Girolami U, Kieran MW. Prognostic value of tumor microinvasion and metalloproteinases expression in intracranial pediatric ependymomas. J Neuropathol Exp Neurol 2008; 67:911-20. [PMID: 18716553 PMCID: PMC2686114 DOI: 10.1097/nen.0b013e318184f413] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Ependymomas are common pediatric intracranial neoplasms that often appear well circumscribed on imaging but may recur when they are treated by surgical resection alone. The current World Health Organization histological grading system does not accurately predict clinical behavior. The aim of this study was to identify histological and immunohistochemical features that correlate with clinical course in patients with ependymomas treated by gross total resection. We analyzed 41 pediatric ependymomas for microinvasion and correlated immunostaining for the metalloproteinase (MMP)-2 and MMP14 and for ezrin and bcl-2 with clinical outcome. Gross total resection had a significantly positive effect on overall survival and progression-free survival. In 28 patients who underwent gross total resection, microinvasion correlated with poor overall survival (p = 0.003) and progression-free survival (p = 0.03). Gross totally resected tumors with high expression of MMP2 and MMP14 had significantly shorter overall survival. Ezrin staining identified tumor cells invading the adjacent white matter that were not identified by routine stains, but Ezrin staining and bcl-2 staining did not provide strong prognostic correlations. The data indicate that tumor microinvasion into adjacent brain and tumor expression of MMP2 and MMP14 predict both overall and progression-free survival in pediatric ependymomas, and these are useful prognostic markers that may help stratify patients for adjuvant therapies.
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Affiliation(s)
- Matija Snuderl
- Pathology Service, Massachusetts General Hospital, Boston, MA 02114, USA.
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Tagscherer KE, Fassl A, Campos B, Farhadi M, Kraemer A, Böck BC, Macher-Goeppinger S, Radlwimmer B, Wiestler OD, Herold-Mende C, Roth W. Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 2008; 27:6646-56. [DOI: 10.1038/onc.2008.259] [Citation(s) in RCA: 172] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, Wick W. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 2008; 14:2900-8. [PMID: 18483356 PMCID: PMC2430468 DOI: 10.1158/1078-0432.ccr-07-1719] [Citation(s) in RCA: 274] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase, which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.
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Affiliation(s)
- Jann N Sarkaria
- Department of Radiation Oncology and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
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Kato N, Motoyama T. Overexpression of osteopontin in clear cell carcinoma of the ovary: close association with HNF-1beta expression. Histopathology 2008; 52:682-8. [PMID: 18393978 DOI: 10.1111/j.1365-2559.2008.03006.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
AIMS Transcription factor hepatocyte nuclear factor (HNF)-1beta is selectively expressed in clear cell carcinoma (CCC) of the ovary. One of the potential HNF-1beta target genes is osteopontin (OPN). Although elevation of OPN mRNA has been reported in CCC, it remains unclear whether CCC cells overexpress OPN protein. The aim was to investigate the expression of OPN protein and its correlation with HNF-1beta status in CCC. METHODS AND RESULTS Three CCC and two serous adenocarcinoma (SA) cell lines were evaluated for expression of OPN by reverse transcriptase-polymerase chain reaction and immunocytochemistry. OPN expression, at both the mRNA and protein levels, was higher in the three CCCs than in the two SAs. HNF-1beta expression was detected in the CCCs but not in the SAs. Subsequently, 60 surgical specimens (30 CCCs and 30 SAs) were examined immunohistochemically for expression of OPN and HNF-1beta. All 30 CCCs showed immunopositivity for both OPN and HNF-1beta. The 12 (40%) CCCs with a high OPN score all had a high HNF-1beta score. In contrast, SAs rarely showed immunoreactivity for OPN or HNF-1beta. CONCLUSIONS OPN expression is elevated in ovarian CCC and is closely associated with HNF-1beta overexpression. HNF-1beta is likely to participate in OPN up-regulation in CCC.
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Affiliation(s)
- N Kato
- Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan.
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48
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Lu C, Shervington A. Chemoresistance in gliomas. Mol Cell Biochem 2008; 312:71-80. [PMID: 18259841 DOI: 10.1007/s11010-008-9722-8] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Accepted: 01/29/2008] [Indexed: 01/07/2023]
Abstract
Despite improved knowledge and advanced treatments of gliomas, the overall survival rate for glioma patients remains low. Gliomas comprise of significant cell heterogeneity that contains a large number of multidrug resistant (MDR) phenotypes and cancer stem cells (CSCs), a combination that may contribute to the resistance to treatment. This article reviews the MDR related genes, major-vault protein (MVP), anti-apoptotic protein (Bcl-2) and the molecular mechanisms that may contribute to chemoresistance, in addition to the upregulated MDR phenotypes present in CSCs that has recently been identified in gliomas. Moreover, future potential therapies that modulate MDR phenotypes and CSCs are also reviewed. An improved understanding of MDR may lead to a combined treatment, targeting both CSCs and their protective MDR phenotypes leading eventually to attractive strategies for the treatment of gliomas.
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Affiliation(s)
- Chen Lu
- Brain Tumour North West, Faculty of Science, University of Central Lancashire, Preston, UK
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Bögler O, Mikkelsen T. Angiogenesis and apoptosis in glioma: two arenas for promising new therapies. J Cell Biochem 2008; 96:16-24. [PMID: 16052525 DOI: 10.1002/jcb.20475] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
New therapies for gliomas are urgently needed in view of the very marginal increase in patient survival that has been achieved over the past two decades, which is only somewhat mitigated by improvements in quality of life. Two relatively recent fields of research that hold out great promise in this area, are angiogenesis and apoptosis. Depriving growing tumors of the blood supply they need, or tipping the balance in the cancer cell towards cell death, both provide conceptually elegant approaches to therapy, with the hope of great efficacy and little toxicity. However, attempts at successfully translating exciting laboratory findings to the clinic have been slowed by the complexity of the underlying biology. In this article we examine some of the issues that have impeded progress, and examine the potential role that integrins may play as targets, with a role in both angiogenesis and apoptosis.
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Affiliation(s)
- Oliver Bögler
- William and Karen Davidson Laboratory of Brain Tumor Biology, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202, USA.
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50
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Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2008; 21:2683-710. [PMID: 17974913 DOI: 10.1101/gad.1596707] [Citation(s) in RCA: 1725] [Impact Index Per Article: 101.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.
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Affiliation(s)
- Frank B Furnari
- Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California 92093, USA
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