DIFFERENTIATION AND APOPTOSIS IN MALIGNANT NEUROBLASTOMA

Summary

Principal Investigator: Swapan Ray
Affiliation: University of South Carolina
Country: USA
Abstract: DESCRIPTION (provided by applicant): 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

  1. doi Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Neurochem Res 34:87-101. 2009
  2. doi Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma
    Gerald C Wallace
    Department of Neurosciences and MUSC Brain and Spine Tumor Program, Medical University of South Carolina, Charleston, SC 29425, USA
    Metab Brain Dis 28:355-66. 2013
  3. pmc Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29209, USA
    Cancer 116:164-76. 2010
  4. pmc Estrogen receptor agonists and estrogen attenuate TNF-α-induced apoptosis in VSC4.1 motoneurons
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, South Carolina 29425, USA
    J Endocrinol 208:171-82. 2011
  5. pmc Survivin knockdown and concurrent 4-HPR treatment controlled human glioblastoma in vitro and in vivo
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neuro Oncol 12:1088-101. 2010
  6. pmc Calpain inhibition attenuates intracellular changes in muscle cells in response to extracellular inflammatory stimulation
    Kenkichi Nozaki
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Exp Neurol 225:430-5. 2010
  7. pmc Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis
    M Kelly Guyton
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 88:2398-408. 2010
  8. pmc Knockdown of hTERT and concurrent treatment with interferon-gamma inhibited proliferation and invasion of human glioblastoma cell lines
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA
    Int J Biochem Cell Biol 42:1164-73. 2010
  9. pmc The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors
    Arabinda Das
    Department of Neurosciences Division of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA
    J Pineal Res 48:157-69. 2010
  10. pmc Combination of hTERT knockdown and IFN-gamma treatment inhibited angiogenesis and tumor progression in glioblastoma
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA
    Clin Cancer Res 15:7186-95. 2009

Scientific Experts

  • Swapan K Ray
  • Naren L Banik
  • Arabinda Das
  • Surajit Karmakar
  • Joseph George
  • Nishant Mohan
  • Joshua A Smith
  • Subhasree Roy Choudhury
  • Supriti Samantaray
  • Ran Zhang
  • Jonathan T Butler
  • Rajiv Janardhanan
  • Sunil J Patel
  • Eric A Sribnick
  • Gerald C Wallace
  • S Samantaray
  • Azizul Haque
  • Catherine P Haar
  • Abhay K Varma
  • M Kelly Guyton
  • N L Banik
  • Russel J Reiter
  • Pierre Giglio
  • Mrinmay Chakrabarti
  • Md Motarab Hossain
  • Kenkichi Nozaki
  • John J Woodward
  • Mary K Guyton
  • V H Knaryan
  • S Karmakar
  • Varduhi H Knaryan
  • Denise D Matzelle
  • Amber M Mittendorf
  • W Alex Vandergrift
  • Yaenette N Dixon-Mah
  • Mehrab Khandkar
  • Preetha Hebbar
  • William A Vandergrift
  • Cameron Gibson
  • C Le Gal
  • Matthew J Pava
  • Misty McDowell
  • Jun Inoue
  • Saurav Brahmachari
  • Angelo M Del Re
  • Mitsuyoshi Azuma
  • S Roy Choudhury
  • Kristin A Davis
  • Craig C Beeson
  • Anurag Deeconda
  • Amogh Belagodu
  • Anil V Yallapragada
  • D Denise Matzelle
  • Austin Younger
  • Laela M Hajiaghamohseni
  • M K Guyton
  • D D Matzelle
  • M Foster Olive

Detail Information

Publications66

  1. doi Molecular mechanisms of the combination of retinoid and interferon-gamma for inducing differentiation and increasing apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda 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...
  2. doi Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma
    Gerald C Wallace
    Department of Neurosciences and MUSC Brain and Spine Tumor Program, Medical University of South Carolina, Charleston, SC 29425, USA
    Metab Brain Dis 28:355-66. 2013
    ....
  3. pmc Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29209, USA
    Cancer 116:164-76. 2010
    ....
  4. pmc Estrogen receptor agonists and estrogen attenuate TNF-α-induced apoptosis in VSC4.1 motoneurons
    Arabinda Das
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, South Carolina 29425, USA
    J Endocrinol 208:171-82. 2011
    ..Our data strongly imply that PPT, DPN, or EST can be used as effective neuroprotective agents to attenuate motoneuron death in ALS and SCI...
  5. pmc Survivin knockdown and concurrent 4-HPR treatment controlled human glioblastoma in vitro and in vivo
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neuro Oncol 12:1088-101. 2010
    ..Our data demonstrated that survivin knockdown and concurrent 4-HPR treatment could be a novel therapeutic strategy for controlling growth of human glioblastomas...
  6. pmc Calpain inhibition attenuates intracellular changes in muscle cells in response to extracellular inflammatory stimulation
    Kenkichi Nozaki
    Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Exp Neurol 225:430-5. 2010
    ..Thus, our results indicate that calpain inhibition plays a pivotal role in attenuating muscle cell damage from inflammatory stimulation due to IFN-γ, and this may suggest calpain as a possible therapeutic target in IIMs...
  7. pmc Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis
    M Kelly Guyton
    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    J Neurosci Res 88:2398-408. 2010
    ..These results indicate that calpain inhibition may offer a novel therapeutic avenue for treating EAE and MS...
  8. pmc Knockdown of hTERT and concurrent treatment with interferon-gamma inhibited proliferation and invasion of human glioblastoma cell lines
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA
    Int J Biochem Cell Biol 42:1164-73. 2010
    ..Therefore, the combination of hTERT siRNA and IFN-gamma offers a potential therapeutic strategy for controlling growth of human glioblastoma cells...
  9. pmc The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors
    Arabinda Das
    Department of Neurosciences Division of Neurology, Medical University of South Carolina, Charleston, SC 29425, USA
    J Pineal Res 48:157-69. 2010
    ..1 motoneuron apoptosis. Results suggest that neuroprotection rendered by melatonin to motoneurons is receptor mediated and melatonin may be an effective neuroprotective agent to attenuate motoneuron death in CNS injuries and diseases...
  10. pmc Combination of hTERT knockdown and IFN-gamma treatment inhibited angiogenesis and tumor progression in glioblastoma
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA
    Clin Cancer Res 15:7186-95. 2009
    ..IFN-gamma modulates several cellular activities, including signaling pathways and cell cycle, through transcriptional regulation...
  11. pmc Genistein induces receptor and mitochondrial pathways and increases apoptosis during BCL-2 knockdown in human malignant neuroblastoma SK-N-DZ cells
    Joseph George
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, USA
    J Neurosci Res 88:877-86. 2010
    ..Therefore, this strategy could serve as a potential therapeutic regimen to inhibit the growth of human malignant neuroblastoma...
  12. doi Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplifi
    Subhasree Roy Choudhury
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Building 2, Room C11, 6439 Garners Ferry Road, Columbia, SC 29209, USA
    Invest New Drugs 28:812-24. 2010
    ..Thus, this combination of drugs could be a potential therapeutic strategy against human malignant neuroblastoma cells having N-Myc amplification or non-amplification...
  13. pmc Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-gamma
    Joshua A Smith
    Department of Neurosciences, Medical University of South Carolina, Charleston, 29425, USA
    Brain Res 1301:163-70. 2009
    ..In conclusion, our studies suggest that PTEN inactivation may be used as an important parameter for evaluation of the efficacy of estrogen in prevention of neuronal loss in neurodegenerative disorders...
  14. pmc Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death
    Joshua A Smith
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, 310 Clinical Sciences Building, Charleston, SC 29425, USA
    Neurochem Res 36:1587-93. 2011
    ..We found that estrogen or estrogen receptor agonists upregulated expression of ERs. Overall, results indicate that estrogen receptor agonist or estrogen uses a receptor mediated pathway to protect microglia from LPS toxicity...
  15. pmc Inhibition of cysteine proteases in acute and chronic spinal cord injury
    Swapan K Ray
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29209, USA
    Neurotherapeutics 8:180-6. 2011
    ..Recent studies suggest that physiological hormones, such as estrogen and melatonin, can be successfully used for prevention of neurodegeneration and preservation of motor function in acute SCI as well as in chronic SCI in rats...
  16. pmc Survivin knockdown increased anti-cancer effects of (-)-epigallocatechin-3-gallate in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells
    Md Motarab Hossain
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Exp Cell Res 318:1597-610. 2012
    ..Collectively, survivin silencing potentiated anti-cancer effects of EGCG in human malignant neuroblastoma cells having survivin overexpression...
  17. pmc Alterations in expression of specific microRNAs by combination of 4-HPR and EGCG inhibited growth of human malignant neuroblastoma cells
    Mrinmay Chakrabarti
    University of South Carolina School of Medicine, Department of Pathology, Microbiology, and Immunology, Columbia, SC 29209, USA
    Brain Res 1454:1-13. 2012
    ..Overexpression of miR-93 and miR-7-1, respectively, decreased and increased efficacy of treatments. Thus, alterations in expression of specific OGmiRs and TSmiRs by 4-HPR and EGCG inhibited growth of malignant neuroblastomas...
  18. doi Drug resistance in glioblastoma: a mini review
    Catherine P Haar
    Divisions of Neurology and Neurosurgery, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
    Neurochem Res 37:1192-200. 2012
    ..The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated...
  19. pmc Synergistic efficacy of a novel combination therapy controls growth of Bcl-x(L) bountiful neuroblastoma cells by increasing differentiation and apoptosis
    Nishant Mohan
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
    Cancer Biol Ther 12:846-54. 2011
    ....
  20. pmc Combination of N-(4-hydroxyphenyl) retinamide and apigenin suppressed starvation-induced autophagy and promoted apoptosis in malignant neuroblastoma cells
    Nishant Mohan
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neurosci Lett 502:24-9. 2011
    ..Collectively, combination of 4-HPR and APG worked synergistically to suppress autophagy and promote apoptosis in human malignant neuroblastoma cells...
  21. doi Valproic acid induced differentiation and potentiated efficacy of taxol and nanotaxol for controlling growth of human glioblastoma LN18 and T98G cells
    Subhasree Roy Choudhury
    Department of Pathology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    Neurochem Res 36:2292-305. 2011
    ..The combination of VPA and NTX most effectively controlled the growth of LN18 and T98G cells. Therefore, this combination of drugs can be used as an effective treatment for controlling growth of human glioblastoma cells...
  22. doi Combination of taxol and Bcl-2 siRNA induces apoptosis in human glioblastoma cells and inhibits invasion, angiogenesis and tumour growth
    Joseph George
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA
    J Cell Mol Med 13:4205-18. 2009
    ..Therefore, the combination of a low dose of taxol and Bcl-2 siRNA is a promising therapeutic strategy for controlling the aggressive growth of human glioblastoma...
  23. doi SU5416 and EGCG work synergistically and inhibit angiogenic and survival factors and induce cell cycle arrest to promote apoptosis in human malignant neuroblastoma SH-SY5Y and SK-N-BE2 cells
    Nishant Mohan
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA
    Neurochem Res 36:1383-96. 2011
    ..Taken together, this combination of drugs can be a promising therapeutic strategy for controlling the growth of human malignant neuroblastoma cells...
  24. ncbi Molecular mechanisms of anti-cancer action of garlic compounds in neuroblastoma
    Surajit Karmakar
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, USA
    Anticancer Agents Med Chem 11:398-407. 2011
    ..Further studies should be conducted to establish the clinical expediency of garlic-derived OSCs for treatment of malignant neuroblastoma in humans...
  25. pmc Calpain inhibition protected spinal cord motoneurons against 1-methyl-4-phenylpyridinium ion and rotenone
    S Samantaray
    Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309 CSB, PO Box 250606, Charleston, SC 29425, USA
    Neuroscience 192:263-74. 2011
    ..Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy...
  26. ncbi Modulatory effects of acetazolomide and dexamethasone on temozolomide-mediated apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda 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...
  27. ncbi Methylprednisolone and indomethacin inhibit oxidative stress mediated apoptosis in rat C6 glioblastoma cells
    Arabinda 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...
  28. pmc Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cells
    Mary 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...
  29. pmc Combination of N-(4-hydroxyphenyl) retinamide and genistein increased apoptosis in neuroblastoma SK-N-BE2 and SH-SY5Y xenografts
    S 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...
  30. pmc N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53
    Rajiv 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...
  31. pmc 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 cells
    Nishant 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...
  32. pmc Bcl-2 inhibitor and apigenin worked synergistically in human malignant neuroblastoma cell lines and increased apoptosis with activation of extrinsic and intrinsic pathways
    Surajit 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...
  33. pmc Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels
    Eric 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...
  34. ncbi Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice
    Surajit 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...
  35. ncbi Intracranial stereotaxic cannulation for development of orthotopic glioblastoma allograft in Sprague-Dawley rats and histoimmunopathological characterization of the brain tumor
    Surajit Karmakar
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Neurochem Res 32:2235-42. 2007
    ....
  36. ncbi Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis
    Arabinda 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...
  37. ncbi Direct evidence for calpain involvement in apoptotic death of neurons in spinal cord injury in rats and neuroprotection with calpain inhibitor
    Eric 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...
  38. ncbi Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda 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...
  39. ncbi Molecular mechanism of inositol hexaphosphate-mediated apoptosis in human malignant glioblastoma T98G cells
    Surajit 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...
  40. ncbi 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 apoptosis
    Ran Zhang
    Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA
    Neurochem Res 32:2194-202. 2007
    ....
  41. ncbi Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells
    Surajit 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...
  42. pmc The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats
    S 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...
  43. pmc 5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells
    Surajit 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...
  44. ncbi Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cells
    Surajit 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...
  45. ncbi Currently evaluated calpain and caspase inhibitors for neuroprotection in experimental brain ischemia
    Swapan 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...
  46. ncbi Mechanism of apoptosis with the involvement of calpain and caspase cascades in human malignant neuroblastoma SH-SY5Y cells exposed to flavonoids
    Arabinda 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...
  47. ncbi Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells
    Surajit 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...
  48. ncbi 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) cells
    Ran 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...
  49. ncbi Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda 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...
  50. pmc N-(4-Hydroxyphenyl) retinamide potentiated paclitaxel for cell cycle arrest and apoptosis in glioblastoma C6 and RG2 cells
    Rajiv 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...
  51. pmc Retinoids induce differentiation and downregulate telomerase activity and N-Myc to increase sensitivity to flavonoids for apoptosis in human malignant neuroblastoma SH-SY5Y cells
    Arabinda 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...
  52. pmc Involvement of calpain in the process of Jurkat T cell chemotaxis
    Jonathan 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...
  53. pmc Differential sensitivity of human glioblastoma LN18 (PTEN-positive) and A172 (PTEN-negative) cells to Taxol for apoptosis
    Ran 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...
  54. ncbi New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimer's disease: cathepsin inhibitors as potential therapeutics
    Azizul 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...
  55. pmc N-(4-Hydroxyphenyl) retinamide induced both differentiation and apoptosis in human glioblastoma T98G and U87MG cells
    Arabinda 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...
  56. pmc Time-dependent increases in protease activities for neuronal apoptosis in spinal cords of Lewis rats during development of acute experimental autoimmune encephalomyelitis
    Arabinda 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...
  57. pmc Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stress
    Arabinda 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...
  58. doi Bcl-2 siRNA augments taxol mediated apoptotic death in human glioblastoma U138MG and U251MG cells
    Joseph 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...
  59. pmc N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-gamma sensitivity for apoptosis in human glioblastoma cells
    Rajiv 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...
  60. ncbi Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice
    Surajit 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...
  61. pmc Melatonin attenuates calpain upregulation, axonal damage and neuronal death in spinal cord injury in rats
    Supriti 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...
  62. ncbi Spinal cord degeneration in C57BL/6N mice following induction of experimental parkinsonism with MPTP
    Supriti 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...
  63. ncbi Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells
    Azizul 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...