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Genomes and Genes | DIFFERENTIATION AND APOPTOSIS IN MALIGNANT NEUROBLASTOMASummaryPrincipal Investigator: Swapan Ray Affiliation: University of South Carolina Country: USA Abstract: Neuroblastoma is the most common malignant disease of early childhood. Infants younger than 1 year have a good prognosis, while older patients show metastatic neuroblastoma with poor outcome and death. Because current treatment strategies are ineffective in children older than 1 year, innovative therapeutic strategies are urgently needed. This proposal aims to develop a combination therapy to control the growth of malignant neuroblastoma. Our preliminary results indicate that retinoids, such as all-trans-retinoic acid (ATRA), 13-cis-retinoicacid (13-CRA), and fenretinide [N-(4-hydroxyphenyl) retinamide or 4-HPR] induce differentiation in 5 human neuroblastoma cell lines (SH-SY5Y, SK-N-BE2, SK-N-DZ, IMR-32, and SK-N-MC). Also, flavonoids, such as apigenin (APG), (-)-epigallocatechin (EGG), (-)-epigallocatechin-3-gallate (EGCG), and genistein (GST), induce apoptosis. Interestingly, neuroblastoma cells differentiated with specifically 4- HPR became more sensitive to flavonoids, especially GST, for induction of apoptosis with increased ratio of bax:bcl-2 and upregulation of calpain and caspases. Treatment of neuroblastoma xenografts in nude mice with a combination of low doses of 4-HPR and GST regressed tumors with induction of differentiation and apoptosis. We hypothesize that (1) 4-HPR induces differentiation and down regulates survival factors; (2) GST induces apoptosis inhibiting survival factors and activating cysteine proteases and enhances apoptosis in differentiated cells; (3) treatment of neuroblastoma xenografts with 4-HPR and GST induces differentiation and enhances apoptosis. Our central hypothesis is that promotion of differentiation with a selective retinoid down regulates telomerase and survival proteins, and sensitizes differentiated cells to a selective flavonoid for enhancing apoptosis with activation of cysteine proteases. The objective is to use a combination therapy for differentiation and apoptosis in neuroblastoma cells in culture as well in ectopic and orthotopic xenografted animal models. To achieve this objective, we propose the following specific aims: Specific Aim 1: To determine the morphological and biochemical features of neuronal differentiation in five human neuroblastoma cell lines in response to selected retinoids. Specific Aim 2: To examine the induction of apoptosis in five human neuroblastoma cell lines following treatment with selected flavonoids and enhancement of apoptosis in differentiated cells. Specific Aim 3: To determine the efficacy of combination of a selected retinoid and a selected flavonoid for induction of differentiation and enhancement of apoptosis in neuroblastoma in ectopic and orthotopic xenografts in athymic nude mice. Success of our therapeutic strategy can form a basis for treatment of neuroblastoma in humans. Funding Period: 2006-08-02 - 2010-12-31 more information: NIH RePORT Top Publications
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Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cellsAzizul Haque
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
Cancer Immunol Immunother 56:615-25. 2007..Taken together, this study suggests that induction of apoptosis and immune components of the HLA class II pathway by ATRA plus IFN-gamma may be a promising chemoimmunotherapeutic strategy for treatment of human malignant glioblastoma...
N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-gamma sensitivity for apoptosis in human glioblastoma cellsRajiv Janardhanan
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, P O Box 250606, Charleston, SC 29425, USA
Cancer Lett 261:26-36. 2008..Hence, combination of 4-HPR and IFN-gamma should be considered for controlling growth of different human glioblastoma cells...
Bcl-2 siRNA augments taxol mediated apoptotic death in human glioblastoma U138MG and U251MG cellsJoseph George
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
Neurochem Res 34:66-78. 2009..Thus, combination of taxol and Bcl-2 siRNA offers a novel therapeutic strategy for controlling the malignant growth of human glioblastoma cells...- Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cellsArabinda Das
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 34:87-101. 2009..Taken together, our results showed that retinoid induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to IFN-gamma for increasing apoptosis in human glioblastoma cells... - Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stressArabinda Das
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
J Pineal Res 45:117-24. 2008..The results suggest that melatonin may be an effective cytoprotective agent against glutamate excitotoxicity and oxidative stress in CNS injuries and diseases... - Modulatory effects of acetazolomide and dexamethasone on temozolomide-mediated apoptosis in human glioblastoma T98G and U87MG cellsArabinda Das
Department of Neurosciences Neurology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
Cancer Invest 26:352-8. 2008..Interestingly, ACZ pretreatment enhanced apoptosis while DXM pretreatment decreased apoptosis. These results suggest that combination chemotherapy with ACZ and TMZ may control inflammation and enhance apoptosis in glioblastoma... - Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitisArabinda Das
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
J Neurosci Res 86:2992-3001. 2008..From these findings, we conclude that increases in calpain and caspase activities play crucial roles in neuronal apoptosis during the development of acute EAE... - N-(4-Hydroxyphenyl) retinamide induced both differentiation and apoptosis in human glioblastoma T98G and U87MG cellsArabinda Das
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Brain Res 1227:207-15. 2008..Taken together, these results strongly suggested that 4-HPR could be used at low doses for induction of both differentiation and apoptosis in human glioblastoma cells... - New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer's disease: cathepsin inhibitors as potential therapeuticsAzizul Haque
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
CNS Neurol Disord Drug Targets 7:270-7. 2008..This article also focused on the role of cathepsin inhibitors as disease-modifying treatment strategies that could halt, or even prevent, this devastating neurological disorder... - Differential sensitivity of human glioblastoma LN18 (PTEN-positive) and A172 (PTEN-negative) cells to Taxol for apoptosisRan Zhang
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Brain Res 1239:216-25. 2008..As a single chemotherapy, Taxol might be more efficacious in PTEN-positive glioblastoma than in PTEN-negative glioblastoma. Thus, our study showed differential sensitivity of PTEN-positive and PTEN-negative glioblastoma cells to Taxol... - Involvement of calpain in the process of Jurkat T cell chemotaxisJonathan T Butler
Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
J Neurosci Res 87:626-35. 2009..These studies provide evidence for the involvement of calpain in the mechanisms of chemotaxis and warrants further exploration in MS patient and EAE animal samples... - Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cellsArabinda Das
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Int J Oncol 34:757-65. 2009..Based on our observation, we conclude that combination of a retinoid and a flavonoid worked synergistically for controlling the malignant growth of human neuroblastoma cells... - N-(4-Hydroxyphenyl) retinamide potentiated paclitaxel for cell cycle arrest and apoptosis in glioblastoma C6 and RG2 cellsRajiv Janardhanan
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA
Brain Res 1268:142-53. 2009..g., calpain, cathepsins, caspase-8, caspase-3). Hence, the combination of 4-HPR and PTX can be considered as an effective therapeutic strategy for controlling the growth of heterogeneous glioblastoma cell populations... - Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channelsEric A Sribnick
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
Brain Res 1276:159-70. 2009..1 cells through effects on L-type Ca(2+) channels, inhibiting Ca(2+) influx as well as activation of the pro-apoptotic proteases calpain and caspase-3... - Bcl-2 inhibitor HA14-1 and genistein together adeptly down regulated survival factors and activated cysteine proteases for apoptosis in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cellsNishant Mohan
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
Brain Res 1283:155-66. 2009..Thus, combination of HA and GST could serve as a promising therapeutic strategy for increasing apoptosis in different human malignant neuroblastoma cells... - N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53Rajiv Janardhanan
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA
Biochem Pharmacol 78:1105-14. 2009..These results suggested that combination of 4-HPR and GST could be effective for controlling the growth of heterogeneous human neuroblastoma cell populations... - Combination of N-(4-hydroxyphenyl) retinamide and genistein increased apoptosis in neuroblastoma SK-N-BE2 and SH-SY5Y xenograftsS Karmakar
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA
Neuroscience 163:286-95. 2009..Results demonstrated that combination of 4-HPR and GST induced multiple molecular mechanisms for apoptosis and thus could be highly effective for inhibiting growth of malignant neuroblastoma in preclinical animal models... - Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cellsMary K Guyton
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
J Neurochem 110:1895-907. 2009..Thus, these data suggest calpain as a promising target for treating EAE and MS... - Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude miceSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
Cancer 112:596-607. 2008..As a new treatment strategy, the combination of all-trans retinoic acid (ATRA) and paclitaxel was explored for controlling the growth of glioblastoma U87MG xenografts... - Melatonin attenuates calpain upregulation, axonal damage and neuronal death in spinal cord injury in ratsSupriti Samantaray
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
J Pineal Res 44:348-57. 2008..Taken together, this study strongly suggested that MEL could be an effective neuroprotective agent for treatment of SCI... - Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTPSupriti Samantaray
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
J Neurochem 104:1309-20. 2008..Such extra-nigral neurodegeneration in Parkinson's disease indicated novel molecular mechanism preceding nigrostriatal degeneration and suggested designing broad therapeutic intervention for this complex movement disorder... - Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cellsSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 323K, P.O. Box 250606, Charleston, SC 29425, USA
Neurosci Lett 407:53-8. 2006..Our results strongly suggest that CCM induced both receptor-mediated and mitochondria-mediated proteolytic mechanisms for induction of apoptosis in T98G cells... - Mechanism of apoptosis with the involvement of calpain and caspase cascades in human malignant neuroblastoma SH-SY5Y cells exposed to flavonoidsArabinda Das
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Int J Cancer 119:2575-85. 2006..Thus, plant-derived flavonoids cause cell death with activation of proteolytic activities of calpain and caspases in SH-SY5Y cells, and therefore serve as potential therapeutic agents for controlling the growth of neuroblastoma... - Currently evaluated calpain and caspase inhibitors for neuroprotection in experimental brain ischemiaSwapan K Ray
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Curr Med Chem 13:3425-40. 2006..However, further investigations are necessary for improvements in the structural design of calpain and caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trials in the future... - Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cellsSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 323K, PO Box 250606, Charleston, SC 29425, USA
Apoptosis 12:671-84. 2007..Results strongly suggested that the garlic compounds DAS and DADS suppressed anti-apoptotic factors and activated calpain and intrinsic caspase cascade for apoptosis in SH-SY5Y cells... - 5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cellsSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 323K, Charleston, SC 29425, USA
Neurosci Lett 415:242-7. 2007..The results suggested that 5-ALA-PDT induced apoptosis in U87MG cells by suppression of survival signals and activation of proteolytic pathways. Thus, 5-ALA-PDT can be an effective strategy for inducing apoptosis in glioblastoma... - The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis ratsS Samantaray
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309 CSB, P O Box 250606, Charleston, SC 29425, USA
Neuroscience 146:741-55. 2007..Moreover, rotenone-induced degeneration of SC motoneuron in this model of experimental Parkinsonism progressed with upregulation of calpain and caspase-3... - Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cellsSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 32:2103-13. 2007..Results show that CCM is an effective therapeutic agent for suppression of anti-apoptotic factors and activation of calpain and caspase proteolytic cascades for apoptosis in human malignant glioblastoma cells... - Methylprednisolone and indomethacin inhibit oxidative stress mediated apoptosis in rat C6 glioblastoma cellsArabinda Das
Department of Neurosciences, Medical University of South Carolina MUSC, 96 Jonathan Lucas Street, Suite 323K, P O Box 250606, Charleston, SC 29425, USA
Neurochem Res 32:1849-56. 2007..Thus, pretreatment of glioblastoma with an anti-inflammatory agent, either steroidal or non-steroidal, may compromise the action of a chemotherapeutic agent that mediates therapeutic action via oxidative stress... - Combination of all-trans retinoic acid and interferon-gamma suppressed PI3K/Akt survival pathway in glioblastoma T98G cells whereas NF-kappaB survival signaling in glioblastoma U87MG cells for induction of apoptosisRan Zhang
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 32:2194-202. 2007.... - Molecular mechanism of inositol hexaphosphate-mediated apoptosis in human malignant glioblastoma T98G cellsSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 32:2094-102. 2007..Collectively, our results demonstrated that IP6 down regulated the survival factors BIRC-2 and telomerase and upregulated calpain and caspase-3 activities for apoptosis in T98G cells... - Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cellsArabinda Das
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Cancer 110:1083-95. 2007..Garlic-derived organosulfur compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) provide significant protection against carcinogenesis... - Direct evidence for calpain involvement in apoptotic death of neurons in spinal cord injury in rats and neuroprotection with calpain inhibitorEric A Sribnick
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 32:2210-6. 2007..Our current results provide direct in situ evidence for calpain involvement in neuronal death and neuroprotective efficacy of E-64-d in lesion and penumbra in SCI rats... - Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosisArabinda Das
Department of Neurosciences, Medical University of South Carolina, P O Box 250606, Charleston, SC 29425, USA
Neurochem Res 32:2167-83. 2007..This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma... - Intracranial stereotaxic cannulation for development of orthotopic glioblastoma allograft in Sprague-Dawley rats and histoimmunopathological characterization of the brain tumorSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
Neurochem Res 32:2235-42. 2007.... - Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude miceSurajit Karmakar
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 325E, P O Box 250606, Charleston, SC 29425, USA
Apoptosis 12:2077-87. 2007..Our investigation revealed that treatment of glioblastoma T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis... - Combination of all-trans retinoic acid and interferon-gamma upregulated p27(kip1) and down regulated CDK2 to cause cell cycle arrest leading to differentiation and apoptosis in human glioblastoma LN18 (PTEN-proficient) and U87MG (PTEN-deficient) cellsRan Zhang
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
Cancer Chemother Pharmacol 62:407-16. 2008..We used the combination of ATRA and IFN-gamma to control growth of human glioblastoma LN18 (PTEN-proficient) and U87MG (PTEN-deficient) cells and explored any advantage of having PTEN in the cells... - Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cellsArabinda Das
Department of Neurosciences, Medical University of South Carolina MUSC, Charleston, SC, 29425, USA
J Neurooncol 87:9-22. 2008..Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma... - Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathwaysSurajit Karmakar
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
Biochem Biophys Res Commun 388:705-10. 2009..Results showed that combination of HA and APG could be used for downregulation of angiogenic factors and activation of extrinsic and intrinsic pathways of apoptosis in malignant neuroblastoma cells...