Targeting NFĸB mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2.

Abstract

Resistance to chemotherapy remains a significant obstacle in the treatment of hormone- independent breast cancer. Recent evidence suggests that altered sphingolipid signaling through increased sphingosine kinase activity may be an important mediator of breast cancer drug resistance. Sphingosine kinase-1 (Sphk1) is a proposed key regulator of breast cancer tumorigenesis, proliferation and resistance. There is, however, conflicting data on the role of sphingosine kinase-2 (Sphk2) in cancer biology and resistance, with some suggesting that Sphk2 has an opposing role to that of Sphk1. Here, we studied the effects of the novel selective Sphk2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer. ABC294640 blocked both viability and survival at low micromolar IC(50) concentrations in the endocrine therapy-resistant MDA-MB-231 and chemoresistant MCF-7TN-R cell systems. Treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, pharmacological inhibition of Sphk2 induced apoptosis through the intrinsic programmed cell death pathway. Furthermore, ABC294640 also diminished NF-ĸB survival signaling, through decreased activation of the Ser536 phosphorylation site on the p65 subunit. Xenografts of MCF-7TN-R cells growing in immunocompromised mice were utilized to validate the therapeutic efficacy of the sphingosine kinase-2 inhibitor. Treatment with 50 mg of ABC294640/kg completely blocked tumor volume in this model. These results indicate that pharmacological inhibition of Sphk2 with the orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy- resistant breast cancer.

• Authors: James W Antoon, Martin D White, Evelyn M Slaughter, Jennifer L Driver, Hafez S Khalili, Steven Elliott, Charles D Smith, Matthew E Burow, Barbara S Beckman
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 11 Issue 7 Pg. 678-89 (Apr 01 2011) ISSN: 1555-8576 [Electronic] United States
• PMID: 21307639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Pyridines
• Receptors, Estrogen
• 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Protein Serine-Threonine Kinases
• NF-kappa B kinase
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Mice
• Mice, SCID
• Molecular Targeted Therapy
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, genetics)
• Protein Serine-Threonine Kinases (metabolism)
• Pyridines (pharmacology)
• Receptors, Estrogen (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays