Inhibition of sphingosine kinase-2 ablates androgen resistant prostate cancer proliferation and survival.

Abstract

BACKGROUND:

Endogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance.

METHODS:

The novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling.

RESULTS:

It dose-dependently decreased PC-3 and LNCaP cell viability, IC(50) of 28 ± 6.1 μM (p < 0.05) and 25 ± 4.0 μM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC(50) of 14 ± 0.4 μM (p < 0.05) in PC-3 cells and 12 ± 0.9 μM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells.

CONCLUSIONS:

SphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.

• Authors: Matthew M Gestaut, James W Antoon, Matthew E Burow, Barbara S Beckman
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 66 Issue 1 Pg. 174-8 (Feb 2014) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 24905325 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Chemical References

• Androgen Antagonists
• Ki-67 Antigen
• Pyridines
• 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Androgen Antagonists (therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Humans
• Ki-67 Antigen (analysis)
• Male
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, physiology)
• Prostatic Neoplasms (drug therapy, pathology)
• Pyridines (pharmacology)