Brain derived neurotrophic factor protects human neuroblastoma cells from DNA damaging agents.
Neurotrophins are required for survival of neurons during development and may act as survival factors to cells undergoing stress. We tested whether brain derived neurotrophic factor (BDNF) protects neuroblastoma (NB) cells from cytotoxic agents using a model NB cell line, NB 1643, which expresses functional tropomyosin related kinase B (TRKB) following treatment with all-trans-retinoic acid. TRKB is the receptor for BDNF. BDNF increases the EC50 values in survival assays for cisplatin, doxorubicin, and topotecan by two to three fold. Thus, BDNF does indeed protect cells drugs that damage DNA. Cisplatin and doxorubicin are used to treat NB. Topotecan is in clinical studies for the treatment of NB. Since these drugs induce DNA damage, we also investigated whether BDNF might afford protection from gamma irradiation. BDNF also induces more than a two fold resistance to gamma irradiation. Since BDNF protects cells from agents with different mechanisms of damaging DNA and resistance, it seems likely that BDNF may alter a common signaling pathway required for cell death initiation by DNA damaging agents.
Middlemas
D S
DS
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. david.middlemas@stjude.org
Kihl
B K
BK
Moody
N M
NM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D005720:Gamma Rays; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D004273:DNA, Neoplasm; D018696:Neuroprotective Agents; D019772:Topotecan; D004317:Doxorubicin; D002945:Cisplatin