Targeting acid sphingomyelinase with anti-angiogenic chemotherapy Journal Article

Authors: Jacobi, J.; García-Barros, M.; Rao, S.; Rotolo, J. A.; Thompson, C.; Mizrachi, A.; Feldman, R.; Manova, K.; Bielawska, A.; Bielawska, J.; Fuks, Z.; Kolesnick, R.; Haimovitz-Friedman, A.
Article Title: Targeting acid sphingomyelinase with anti-angiogenic chemotherapy
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 1–2 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. © 2016 Elsevier Inc.
Keywords: chemotherapy; endothelial cells; acid sphingomyelinase; anti-angiogenic drugs; ceramide-rich macrodomains
Journal Title: Cellular Signalling
Volume: 29
ISSN: 0898-6568
Publisher: Elsevier Inc.  
Date Published: 2017-01-01
Start Page: 52
End Page: 61
Language: English
DOI: 10.1016/j.cellsig.2016.09.010
PROVIDER: scopus
PMCID: PMC5138150
PUBMED: 27702691
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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