Doxorubicin induces biphasic neurotoxicity to rat cortical neurons.
Doxorubicin (DOX) is an anthracycline anticancer drug considered to be a first line choice in the treatment of breast cancer, childhood solid tumours, soft tissue sarcomas and aggressive lymphomas. Notwithstanding the fact that DOX does not cross the blood-brain barrier, several modified delivery systems have been recently developed to circumvent this obstacle and use DOX as an effective agent against brain tumours. However, the putative effect of DOX at the CNS remains elusive. Thus, the aim of this work was to investigate and characterise the mode of cell death induced by the anticancer agent DOX in cortical neurons. The obtained results indicated that DOX is neurotoxic to serum-free cultures of cortical neurons in a biphasic concentration manner: for concentrations up to 0.5microM, cell death follows an apoptotic pattern, while for higher concentrations apoptosis is inhibited and necrosis becomes dominant. Apoptosis induced by DOX in our model can occur via different pathways. It is expected that the obtained information from this work can provide new clues about the mechanisms of DOX neurotoxicity that may be of great value for preventing its effects in non-target cells.
Lopes
Miguel Angelo
MA
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Portugal. miguelaclopes@yahoo.de
Meisel
Andreas
A
Dirnagl
Ulrich
U
Carvalho
Félix Dias
FD
Bastos
Maria de Lourdes
Mde L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011500:Protein Synthesis Inhibitors; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D004317:Doxorubicin; D003513:Cycloheximide; C505410:Casp3 protein, rat; D053148:Caspase 3