Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance

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Updated: May 23, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

James W Antoon1, Martin D White, Matthew E Burow

  • 1Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Oncology Reports
|April 4, 2012
PubMed

Insights

Sphingosine kinase (Sphk) inhibition combats chemoresistance in breast cancer by disrupting cancer cell survival and proliferation. Targeting Sphk shows promise for treating drug-resistant solid tumors.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Aberrant sphingolipid signaling is a key mechanism of chemoresistance in solid tumors.
  • Sphingosine kinase (Sphk) mediates breast cancer progression, survival, and chemoresistance.
  • The precise mechanisms of Sphk-mediated drug resistance remain largely undefined.

Purpose of the Study:

  • To investigate the effects of sphingosine kinase inhibition on multi-drug-resistant breast cancer cells.
  • To elucidate the role of Sphk in chemoresistance and identify potential therapeutic targets.

Main Methods:

  • Utilized SKI-II, a dual sphingosine kinase isozyme inhibitor.
  • Assessed the impact of SKI-II on sphingolipid signaling, cancer cell proliferation, survival, and viability.
  • Investigated the modulation of the NF-κB pathway, including p65 subunit phosphorylation.

Main Results:

  • SKI-II treatment altered endogenous sphingolipid signaling in resistant breast cancer cells.
  • Pharmacological inhibition of Sphk1/2 decreased cancer cell proliferation, survival, and viability.
  • Sphingosine kinase inhibition induced intrinsic apoptosis via NF-κB pathway modulation, decreasing p65 transcriptional activity.

Conclusions:

  • Sphingosine kinase inhibition effectively reduces proliferation and viability in multi-drug-resistant breast cancer cells.
  • Modulation of the NF-κB pathway by Sphk inhibition contributes to apoptosis induction.
  • Sphingosine kinase represents a potential therapeutic target for overcoming chemoresistance in solid tumors.

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