Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants.
Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK/Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.
Department of Anatomy and Cell Biology, The Brody School of Medicine at East Carolina University, Greenville, NC 27834, United States.
Sarah E
SE
James
Hubert
H
Burden
Russell
R
Burgess
Youmei
Y
Xie
Tao
T
Yang
Stephen M
SM
Massa
Frank M
FM
Longo
Qun
Q
Lu
D000577:Amides / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000633:toxicity*; D001562:Benzimidazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000577:Amides; D000814:Aniline Compounds; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C521938:LM11 compound; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C085348:tau-1 monoclonal antibody; C108830:Y 27632; D005982:Glutathione Transferase; D020742:rhoA GTP-Binding Protein; C022616:thiazolyl blue