title: Inhibition of paclitaxel-induced decreases in calcium signaling.
abstract: Peripheral neuropathy is one of the most severe and irreversible side effects caused by treatment from several chemotherapeutic drugs, including paclitaxel (Taxol®) and vincristine. Strategies are needed that inhibit this unwanted side effect without altering the chemotherapeutic action of these drugs. We previously identified two proteins in the cellular pathway that lead to Taxol-induced peripheral neuropathy, neuronal calcium sensor-1 (NCS-1) and calpain. Prolonged treatment with Taxol induces activation of calpain, degradation of NCS-1, and loss of intracellular calcium signaling. This paper has focused on understanding the molecular basis for prevention of peripheral neuropathy by testing the effects of addition of two candidate compounds to the existing chemotherapeutic drug regime: lithium and ibudilast. We found that the co-administration of either lithium or ibudilast to neuroblastoma cells that were treated with Taxol or vincristine inhibited activation of calpain and the reductions in NCS-1 levels and calcium signaling associated with these chemotherapeutic drugs. The ability of Taxol to alter microtubule formation was unchanged by the addition of either candidate compound. These results allow us to suggest that it is possible to prevent the unnecessary and irreversible damage caused by chemotherapeutic drugs while still maintaining therapeutic efficacy. Specifically, the addition of either lithium or ibudilast to existing chemotherapy treatment protocols has the potential to prevent chemotherapy-induced peripheral neuropathy.
authors.affiliation: Department of Pharmacology, University, New Haven, Connecticut 06520, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Benbow
authors.forename: Taylor
authors.initials: T
authors.lastname: Mann
authors.forename: Camille
authors.initials: C
authors.lastname: Keeler
authors.forename: Chengpeng
authors.initials: C
authors.lastname: Fan
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hodsdon
authors.forename: Elias
authors.initials: E
authors.lastname: Lolis
authors.forename: Brenda
authors.initials: B
authors.lastname: DeGray
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Ehrlich
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects*; D002154:Calpain / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008094:Lithium / Q000494:pharmacology*; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D057054:Molecular Imaging; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology / Q000633:toxicity; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D002154:Calpain; D008094:Lithium; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D017239:Paclitaxel; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D050257:Tubulin Modulators; C101464:frequenin calcium sensor proteins; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles