Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.
Department of Pharmacology, Yale University, New Haven, Connecticut, USA.
Michelle
M
Mo
Ildiko
I
Erdelyi
Klara
K
Szigeti-Buck
Jennifer H
JH
Benbow
Barbara E
BE
Ehrlich
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008094:Lithium / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D007212:Indolizines; D011720:Pyrazoles
D000972:Antineoplastic Agents, Phytogenic; D038362:Glycogen Synthase Kinase 3; D008094:Lithium; D018696:Neuroprotective Agents; D017239:Paclitaxel; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles