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Nerve Excitability Assessment in Chemotherapy-induced Neurotoxicity
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Published on: April 26, 2012

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Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Rita Kramer1, Jacek Bielawski1, Emily Kistner-Griffin1

  • 1*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.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|July 23, 2015
PubMed

Insights

Paclitaxel chemotherapy increases 1-deoxysphingolipids, linked to peripheral neuropathy. These neurotoxic sphingolipids, especially very-long-chain deoxyceramides, are associated with chemotherapy-induced peripheral neuropathy (CIPN) severity in breast cancer patients.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Oncology

Background:

  • Peripheral neuropathy is a significant side effect of paclitaxel and cisplatin chemotherapy.
  • 1-deoxysphingolipids represent a novel class of neurotoxic sphingolipids.
  • These lipids are synthesized when serine palmitoyltransferase utilizes l-alanine instead of l-serine.

Purpose of the Study:

  • To investigate the role of 1-deoxysphingolipids in paclitaxel- and cisplatin-induced peripheral neuropathy.
  • To determine if paclitaxel or cisplatin treatment elevates cellular 1-deoxysphingolipid levels.
  • To explore the association between plasma 1-deoxysphingolipid levels and neuropathy symptoms in breast cancer patients.

Main Methods:

  • Cellular treatment with paclitaxel and cisplatin.
  • Measurement of cellular 1-deoxysphingolipid levels and serine palmitoyltransferase activity.
  • Mass spectrometry analysis of plasma 1-deoxysphingolipid levels in breast cancer patients.
  • Evaluation of neuropathy symptoms using the EORTC QLQ-CIPN20 instrument.

Main Results:

  • Paclitaxel, but not cisplatin, caused a dose-dependent increase in cellular 1-deoxysphingolipids and serine palmitoyltransferase activity.
  • A significant association was found between plasma levels of very-long-chain 1-deoxyceramides (e.g., C24) and the incidence/severity of peripheral neuropathy.
  • The strongest correlation was observed between very-long-chain 1-deoxyceramides and motor neuropathy.

Conclusions:

  • 1-deoxysphingolipids, particularly very-long-chain variants, are implicated as molecular intermediates in paclitaxel-induced peripheral neuropathy.
  • These findings suggest a potential therapeutic target for mitigating chemotherapy-induced peripheral neuropathy.
  • The study highlights the specific role of 1-deoxysphingolipids in paclitaxel neurotoxicity.
Keywords:
1-deoxyceramidechemotherapyserine palmitoyltransferasesphingolipid

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