TY - JOUR
T1 - Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons
AU - Staff, Nathan P.
AU - Podratz, Jewel L.
AU - Grassner, Lukas
AU - Bader, Miranda
AU - Paz, Justin
AU - Knight, Andrew M.
AU - Loprinzi, Charles L.
AU - Trushina, Eugenia
AU - Windebank, Anthony J.
N1 - Funding Information:
This work was supported by NIH – (K08)CA169443 (NPS), NIH – NS40471 (AJW), NIH – ES20715 (ET), NIH – (T32)N5000794 (MB) and NIH – CA124477 (CLL). The authors wish to thank Scott Gamb for his technical assistance with electron microscopy and Kyle Howell for his technical assistance with Western blot analyses.
PY - 2013/12
Y1 - 2013/12
N2 - Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.
AB - Bortezomib is part of a newer class of chemotherapeutic agents whose mechanism of action is inhibition of the proteasome-ubiquitination system. Primarily used in multiple myeloma, bortezomib causes a sensory-predominant axonal peripheral neuropathy in approximately 30% of patients. There are no established useful preventative agents for bortezomib-induced peripheral neuropathy (BIPN), and the molecular mechanisms of BIPN are unknown. We have developed an in vitro model of BIPN using rat dorsal root ganglia neuronal cultures. At clinically-relevant dosages, bortezomib produces a sensory axonopathy as evidenced by whole explant outgrowth and cell survival assays. This sensory axonopathy is associated with alterations in tubulin and results in accumulation of somatic tubulin without changes in microtubule ultrastructure. Furthermore, we observed an increased proportion of polymerized tubulin, but not total or acetylated tubulin, in bortezomib-treated DRG neurons. Similar findings are observed with lactacystin, an unrelated proteasome-inhibitor, which argues for a class effect of proteasome inhibition on dorsal root ganglion neurons. Finally, there is a change in axonal transport of mitochondria induced by bortezomib in a time-dependent fashion. In summary, we have developed an in vitro model of BIPN that recapitulates the clinical sensory axonopathy; this model demonstrates that bortezomib induces an alteration in microtubules and axonal transport. This robust model will be used in future mechanistic studies of BIPN and its prevention.
KW - Bortezomib
KW - Chemotherapy-induced peripheral neuropathy
KW - Dorsal root ganglia
KW - Neurotoxicity
KW - Peripheral neuropathy
KW - Rat
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UR - http://www.scopus.com/inward/citedby.url?scp=84884726313&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2013.09.001
DO - 10.1016/j.neuro.2013.09.001
M3 - Article
C2 - 24035926
AN - SCOPUS:84884726313
SN - 0161-813X
VL - 39
SP - 124
EP - 131
JO - NeuroToxicology
JF - NeuroToxicology
ER -