Computational analysis of the effects of antineoplastic agents on axonal transport.
Axonal transport plays a crucial role in neuronal morphogenesis, survival, and function. Despite its importance, however, the molecular mechanisms of axonal transport remain mostly unknown because a simple and quantitative assay system for axonal transport has been lacking. In order to better characterize the molecular mechanisms involved in axonal transport, we here developed a computer-assisted monitoring system. Using lipophilic fluorochrome chloromethylbenzamido dialkylcarbocyanine (CM-DiI) as a labeling dye, we have successfully labeled membranous organelles in cultured chick dorsal root ganglia neurons. We confirmed that sodium azide, an ATPase inhibitor, and nocodazole, a microtubule-destabilizing agent, markedly suppressed anterograde and retrograde axonal transport of CM-DiI-labeled particles. We further tested the effects of several anti-neoplastic drugs on axonal transport. Paclitaxel, vincristine, cisplatin, and oxaliplatin, all of which are known to be neurotoxic and to cause neurological symptoms, suppressed anterograde and retrograde axonal transport. Another series of anti-neoplastic drugs, including methotrexate and 5-fluorouracil, did not affect the axonal transport. This is the first report of an automated monitoring system for axonal transport. This system will be useful for toxicity assays, characterizing axonal transport, or screening drugs that may modify neuronal functions.
Goshima
Yoshio
Y
Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Japan. goshima@med.yokohama-cu.ac.jp
Usui
Hiroshi
H
Shiozawa
Takahito
T
Hida
Tomonobu
T
Kuraoka
Satoshi
S
Takeshita
Sayumi
S
Yamashita
Naoya
N
Ichikawa
Yasushi
Y
Kamiya
Yoshinori
Y
Gotoh
Takahisa
T
Gotoh
Toshiyuki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D002232:Carbocyanines / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D002945:Cisplatin / Q000494:pharmacology; D019295:Computational Biology; D005456:Fluorescent Dyes / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D009474:Neurons / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D015388:Organelles / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology; D019810:Sodium Azide / Q000494:pharmacology; D012984:Software; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; C101089:CM-DiI; D002232:Carbocyanines; D005456:Fluorescent Dyes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D014750:Vincristine; D019810:Sodium Azide; D017239:Paclitaxel; D002945:Cisplatin; D015739:Nocodazole; D005472:Fluorouracil