Targeting acid sphingomyelinase with anti-angiogenic chemotherapy Academic Article uri icon

Overview

MeSH Major

  • Apoptosis
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Ceramides
  • Germ Cells
  • Radiation, Ionizing

abstract

  • Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase(+/+), but not in asmase(-/-), hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.

publication date

  • January 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5138150

Digital Object Identifier (DOI)

  • 10.1016/j.cellsig.2016.09.010

PubMed ID

  • 27702691

Additional Document Info

start page

  • 52

end page

  • 61

volume

  • 29