title: Docosahexaenoic acid (DHA) sensitizes brain tumor cells to etoposide-induced apoptosis.
abstract: In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: K
authors.initials: K
authors.lastname: Bhat
authors.forename: M
authors.initials: M
authors.lastname: Doucette
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.forename: B
authors.initials: B
authors.lastname: Law
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: E T
authors.initials: ET
authors.lastname: Wong
authors.forename: J X
authors.initials: JX
authors.lastname: Kang
authors.forename: T-C
authors.initials: TC
authors.lastname: Hsieh
authors.forename: S Y
authors.initials: SY
authors.lastname: Qian
authors.forename: E
authors.initials: E
authors.lastname: Wu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008527:Medulloblastoma / Q000188:drug therapy* / Q000473:pathology; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D014157:Transcription Factors; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004281:Docosahexaenoic Acids; D005047:Etoposide; D018960:Hyaluronan Receptors; D051034:Inhibitor of Apoptosis Proteins; D048308:Mitogen-Activated Protein Kinase 14; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D014157:Transcription Factors; C107489:BIRC5 protein, human; C497483:CD44 protein, human; C514215:MNAT1 protein, human; D000095043:Cyclin-Dependent Kinase-Activating Kinase