4.6 Article

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy

Journal

CELLULAR SIGNALLING
Volume 29, Issue -, Pages 52-61

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2016.09.010

Keywords

Chemotherapy; Endothelial cells; Anti-angiogenic drugs; Acid sphingomyelinase; Ceramide-rich macrodomains

Categories

Funding

  1. NIH [CA105125, CA158367, P30 CA008748]

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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 1-2 h 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. (C) 2016 Elsevier Inc. All rights reserved.

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