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Clinical Trial
. 2015 Nov;29(11):4461-72.
doi: 10.1096/fj.15-272567. Epub 2015 Jul 21.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Rita Kramer  1 , Jacek Bielawski  1 , Emily Kistner-Griffin  1 , Alaa Othman  1 , Irina Alecu  1 , Daniela Ernst  1 , Drew Kornhauser  1 , Thorsten Hornemann  2 , Stefka Spassieva  2
Affiliations
Clinical Trial

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

Rita Kramer et al. FASEB J. 2015 Nov.

Abstract

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 µM) and cisplatin (250 nM, 1 µM) 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.

Keywords: 1-deoxyceramide; chemotherapy; serine palmitoyltransferase; sphingolipid.

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Figures

Figure 1.
Figure 1.
The sphingolipid pathway.
Figure 2.
Figure 2.
Paclitaxel treatment increased the levels of 1-deoxysphingolipids in cells. U87 astroglioma cells were treated with increasing concentrations of paclitaxel (A, C, E) or cisplatin (B, D, F) for 24 h. The cells were collected, and cellular lipid extracts were subjected to LC/MS/MS for determining the concentration of: total 1-deoxyceramide (A, B), C24 1-deoxyceramide (C, D), and 1-deoxysphingosine (E, F). The levels of 1-deoxysphingolipids were normalized to the levels of the cellular lipid phosphate. Error bar: range of 2 independent experiments. *P < 0.05, by Student's t test.
Figure 3.
Figure 3.
Paclitaxel treatment increased the expression level of 2 major SPT subunits and the production of 1-deoxysphingolipids in a dose-dependent manner. U87 astroglioma cells were treated with increasing concentrations of paclitaxel (A, B) for 24 h. The cells were collected and expression levels of SPTLC1 (A) and SPTLC 2 (B) were determined on RNA extracts by RT-PCR. Expression levels of the studied genes were normalized to GAPDH. Error bars: 2 independent experiments (3 technical repeats within each experiment). HEK293 cells were metabolically labeled with deuterated l-alanine (C) or l-serine (D) for 24 h. FB1 (30 µM) was used simultaneously with the metabolic label to block the conversion of deuterated 1-deoxysphinganine or deuterated sphinganine to 1-deoxyceramide or ceramide and complex sphingolipids. Increasing concentrations of paclitaxel were used to treat the cells in (C) and (D). Error bars: sd of 3 independent experiments. Overall significance in (C), P < 0.05, by ANOVA.
Figure 4.
Figure 4.
Paclitaxel increases the ratio of l-alanine–derived 1-deoxyceramide over l-serine–derived ceramide in cells. U87 astroglioma cells were treated with paclitaxel for 24 h. The cells were collected and cellular lipid extracts were subjected to LC/MS/MS for determining the concentration of total 1-deoxyceramide and total ceramide. The plot represents the ratios of the absolute amounts of total 1-deoxyceramide and total ceramide normalized to lipid phosphate. Error bar: the range of 2 independent experiments.
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