Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants
Author
James, Sarah E.; Burden, Hubert W.; Burgess, Russell; Xie, Youmei; Tang, Tao; Massa, Stephen M.; Longo, Frank M.; Lu, Qun
Abstract
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withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn.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 p160ROCK/Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75NTR) 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. Originally published Neurotoxicology, Vol. 29, No. 4, July 2008
Subject
Date
2008-07
Citation:
APA:
James, Sarah E., & Burden, Hubert W., & Burgess, Russell, & Xie, Youmei, & Tang, Tao, & Massa, Stephen M., & Longo, Frank M., & Lu, Qun. (July 2008).
Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants.
Neurotoxicology,
29(4),
605-
612. Retrieved from
http://hdl.handle.net/10342/3313
MLA:
James, Sarah E., and Burden, Hubert W., and Burgess, Russell, and Xie, Youmei, and Tang, Tao, and Massa, Stephen M., and Longo, Frank M., and Lu, Qun.
"Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants". Neurotoxicology.
29:4. (605-612),
July 2008.
June 29, 2024.
http://hdl.handle.net/10342/3313.
Chicago:
James, Sarah E. and Burden, Hubert W. and Burgess, Russell and Xie, Youmei and Tang, Tao and Massa, Stephen M. and Longo, Frank M. and Lu, Qun,
"Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants," Neurotoxicology 29, no.
4 (July 2008),
http://hdl.handle.net/10342/3313 (accessed
June 29, 2024).
AMA:
James, Sarah E., Burden, Hubert W., Burgess, Russell, Xie, Youmei, Tang, Tao, Massa, Stephen M., Longo, Frank M., Lu, Qun.
Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology.
July 2008;
29(4):
605-612.
http://hdl.handle.net/10342/3313. Accessed
June 29, 2024.
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Publisher
East Carolina University