title: Withania somnifera water extract as a potential candidate for differentiation based therapy of human neuroblastomas.
abstract: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system. Treatments are often ineffective and have serious side effects. Conventional therapy of neuroblastoma includes the differentiation agents. Unlike chemo-radiotherapy, differentiation therapy shows minimal side effects on normal cells, because normal non-malignant cells are already differentiated. Keeping in view the limited toxicity of Withania somnifera (Ashwagandha), the current study was aimed to investigate the efficacy of Ashwagandha water extract (ASH-WEX) for anti-proliferative potential in neuroblastoma and its underlying signalling mechanisms. ASH-WEX significantly reduced cell proliferation and induced cell differentiation as indicated by morphological changes and NF200 expression in human IMR-32 neuroblastoma cells. The induction of differentiation was accompanied by HSP70 and mortalin induction as well as pancytoplasmic translocation of the mortalin in ASH-WEX treated cells. Furthermore, the ASH-WEX treatment lead to induction of neural cell adhesion molecule (NCAM) expression and reduction in its polysialylation, thus elucidating its anti-migratory potential, which was also supported by downregulation of MMP 2 and 9 activity. ASH-WEX treatment led to cell cycle arrest at G0/G1 phase and increase in early apoptotic population. Modulation of cell cycle marker Cyclin D1, anti-apoptotic marker bcl-xl and Akt-P provide evidence that ASH-WEX may prove to be a promising phytotherapeutic intervention in neuroblatoma related malignancies.
authors: Department of Biotechnology, Guru Nanak Dev University, Amritsar, India.
authors: Hardeep
authors: H
authors: Kataria
authors: Renu
authors: R
authors: Wadhwa
authors: Sunil C
authors: SC
authors: Kaul
authors: Gurcharan
authors: G
authors: Kaur
mesh_terms: D017304:Annexin A5; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D016650:Fluorescein-5-isothiocyanate; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy*; D008517:Phytotherapy / Q000379:methods*; D010936:Plant Extracts / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014867:Water; D032341:Withania / Q000737:chemistry*
chemical_list: D017304:Annexin A5; D017931:DNA Primers; D018840:HSP70 Heat-Shock Proteins; D019006:Neural Cell Adhesion Molecules; D010936:Plant Extracts; C080352:mortalin; D014867:Water; D016650:Fluorescein-5-isothiocyanate; C030693:Ashwagandha
references: Int J Oncol. 2012 Jan;40(1):99-108
references: 21994123
references: Clin Cancer Res. 2008 Oct 1;14(19):6237-45
references: 18829503
references: Cancer Res. 1998 Feb 15;58(4):779-84
references: 9485034
references: Nat Med. 1999 Mar;5(3):286-91
references: 10086383
references: Br J Pharmacol. 2005 Apr;144(7):961-71
references: 15711595
references: Oncogene. 2005 May 5;24(20):3309-18
references: 15735700
references: J Neurosci. 2002 Nov 15;22(22):9868-76
references: 12427843
references: Neuroreport. 2002 Oct 7;13(14):1715-20
references: 12395110
references: J Cell Biol. 1998 Mar 9;140(5):1177-86
references: 9490730
references: J Biol Chem. 1996 Nov 22;271(47):30167-73
references: 8939967
references: Cancer Sci. 2009 Sep;100(9):1740-7
references: 19575749
references: Oncogene. 2003 Nov 27;22(54):8723-30
references: 14647467
references: Br J Cancer. 2002 Feb 12;86(4):540-5
references: 11870534
references: Cell Stress Chaperones. 2002 Jul;7(3):309-16
references: 12482206
references: Endocr Rev. 1999 Aug;20(4):501-34
references: 10453356
references: Cell Tissue Res. 2001 Aug;305(2):171-6
references: 11545254
references: Bioorg Med Chem. 2001 Jun;9(6):1499-507
references: 11408168
references: J Cell Biol. 1998 Oct 5;143(1):195-205
references: 9763431
references: Cell Death Differ. 2002 Nov;9(11):1232-9
references: 12404122
references: Br J Cancer. 2007 Jun 4;96(11):1675-83
references: 17486130
references: Cell Stress Chaperones. 2000 Oct;5(4):291-305
references: 11048652
references: Surgery. 2001 Nov;130(5):834-43
references: 11685193
references: Brain Res. 2008 Apr 8;1203:39-50
references: 18316066
references: Curr Opin Neurobiol. 1997 Oct;7(5):640-6
references: 9384537
references: Oncogene. 2002 Jul 4;21(29):4549-57
references: 12085233
references: J Neurosci Res. 2009 Jul;87(9):2138-44
references: 19224573
references: PLoS One. 2011;6(10):e26236
references: 22022577
references: Cancer Metastasis Rev. 2006 Mar;25(1):9-34
references: 16680569
references: Apoptosis. 2007 Nov;12(11):2115-33
references: 17874299
references: PLoS One. 2012;7(5):e37080
references: 22606332
references: Exp Cell Res. 2004 Aug 1;298(1):268-74
references: 15242781
references: Phytother Res. 2009 Jul;23(7):987-92
references: 19152372
references: Med Chem. 2006 Jul;2(4):431-8
references: 16848757
references: Cancer Res. 1996 May 15;56(10):2237-44
references: 8625291
references: Mol Cell Neurosci. 2011 Nov;48(3):217-24
references: 21864685
references: Dev Genet. 1993;14(2):87-91
references: 8482020
references: Biochem Biophys Res Commun. 2006 Feb 3;340(1):302-8
references: 16364255
references: Phytochemistry. 2008 Feb;69(4):1000-4
references: 18061221
references: Glycobiology. 2008 Feb;18(2):187-94
references: 18077550
references: Oncogene. 2010 May 6;29(18):2739-45
references: 20154722
references: Cancer Res. 2000 Jun 1;60(11):3072-80
references: 10850459
references: Trends Neurosci. 1996 Oct;19(10):422-7
references: 8888519
references: Curr Opin Struct Biol. 1998 Oct;8(5):558-64
references: 9818258
references: J Pathol. 1999 Jul;188(3):289-93
references: 10419598
references: Br J Cancer. 2005 Feb 28;92(4):696-704
references: 15714209
references: Cancer Res. 1995 Jun 15;55(12):2576-82
references: 7780971
references: Exp Cell Res. 1983 Oct;148(1):21-30
references: 6313408
references: Annu Rev Biochem. 2003;72:609-42
references: 12676795
references: Phytother Res. 2010 Oct;24(10):1567-74
references: 20680931
references: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12968-73
references: 19525400
references: J Biol Chem. 2004 Dec 31;279(53):56053-60
references: 15509580
references: Indian J Physiol Pharmacol. 2007 Oct-Dec;51(4):345-53
references: 18476388
references: Cancer Lett. 2008 Apr 8;262(1):37-47
references: 18191020
references: Int J Oncol. 1995 Jul;7(1):69-74
references: 21552808
references: J Natl Cancer Inst. 1997 Sep 3;89(17):1260-70
references: 9293916
references: Nat Cell Biol. 2001 Jul;3(7):650-7
references: 11433297
references: J Neurochem. 1996 Apr;66(4):1641-7
references: 8627321
references: J Biol Chem. 1998 Mar 27;273(13):7675-83
references: 9516473
references: Evid Based Complement Alternat Med. 2011;2011:267614
references: 20007262
references: J Neurosci Res. 2000 Sep 15;61(6):636-45
references: 10972960
references: Cell Cycle. 2006 Jul;5(14):1506-13
references: 16861920
references: Mol Pathol. 1998 Feb;51(1):1-7
references: 9624412
references: Brain Res. 2011 Jan 12;1368:336-45
references: 20974113
references: Science. 2001 Oct 12;294(5541):380-1
references: 11598302
references: Eur J Cancer. 2006 Sep;42(13):2081-91
references: 16919772
references: J Clin Oncol. 2007 Mar 20;25(9):1054-60
references: 17369569
references: J Neurosci. 2004 Jan 28;24(4):843-52
references: 14749429
references: Arch Biochem Biophys. 1994 May 15;311(1):180-90
references: 8185315
references: Phytother Res. 2010 Jun;24(6):859-63
references: 19957250
references: Glia. 1994 Jan;10(1):70-4
references: 8300193
references: Int J Cancer. 1999 Oct 29;83(3):387-92
references: 10495432
references: Mov Disord. 2011 Aug 1;26(9):1639-47
references: 21542017
references: Dev Neurosci. 1989;11(4-5):332-47
references: 2551626
references: J Neurosci. 1991 May;11(5):1163-72
references: 1709204
references: Cancer Res. 2008 Apr 15;68(8):2599-609
references: 18413728
references: Int J Dev Neurosci. 2011 Nov;29(7):701-10
references: 21704149
references: J Biol Chem. 2006 Nov 3;281(44):33606-20
references: 16893893
references: Cancer Res. 2004 Jul 1;64(13):4394-9
references: 15231645
references: Exp Cell Res. 1997 Nov 1;236(2):412-7
references: 9367625
references: J Asian Nat Prod Res. 2012;14(1):39-45
references: 22263592