PMID- 26198449 OWN - NLM STAT- MEDLINE DCOM- 20160211 LR - 20181113 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 29 IP - 11 DP - 2015 Nov TI - Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PG - 4461-72 LID - 10.1096/fj.15-272567 [doi] AB - Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 microM) and cisplatin (250 nM, 1 microM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy. CI - (c) FASEB. FAU - Kramer, Rita AU - Kramer R AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Bielawski, Jacek AU - Bielawski J AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Kistner-Griffin, Emily AU - Kistner-Griffin E AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Othman, Alaa AU - Othman A AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Alecu, Irina AU - Alecu I AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Ernst, Daniela AU - Ernst D AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Kornhauser, Drew AU - Kornhauser D AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland. FAU - Hornemann, Thorsten AU - Hornemann T AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland spassisd@musc.edu thorsten.hornemann@usz.ch. FAU - Spassieva, Stefka AU - Spassieva S AD - *Department of Medicine, Department of Biochemistry and Molecular Biology, and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland spassisd@musc.edu thorsten.hornemann@usz.ch. LA - eng GR - P30 CA138313/CA/NCI NIH HHS/United States GR - P50 DA016511/DA/NIDA NIH HHS/United States GR - 5P50DA016511/DA/NIDA NIH HHS/United States PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150721 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Neurotoxins) RN - 0 (Sphingolipids) RN - P88XT4IS4D (Paclitaxel) SB - IM MH - Adolescent MH - Adult MH - *Breast Neoplasms/blood/drug therapy MH - Cell Line, Tumor MH - Female MH - HEK293 Cells MH - Humans MH - Middle Aged MH - Neurotoxins/*blood MH - Paclitaxel/administration & dosage/*adverse effects MH - *Peripheral Nervous System Diseases/blood/chemically induced MH - Sphingolipids/*blood PMC - PMC4608911 OTO - NOTNLM OT - 1-deoxyceramide OT - chemotherapy OT - serine palmitoyltransferase OT - sphingolipid EDAT- 2015/07/23 06:00 MHDA- 2016/02/13 06:00 CRDT- 2015/07/23 06:00 PHST- 2015/03/10 00:00 [received] PHST- 2015/06/30 00:00 [accepted] PHST- 2015/07/23 06:00 [entrez] PHST- 2015/07/23 06:00 [pubmed] PHST- 2016/02/13 06:00 [medline] AID - fj.15-272567 [pii] AID - 10.1096/fj.15-272567 [doi] PST - ppublish SO - FASEB J. 2015 Nov;29(11):4461-72. doi: 10.1096/fj.15-272567. Epub 2015 Jul 21.