Targeting acid sphingomyelinase with anti-angiogenic chemotherapy

Jeanna Jacobi, Mónica García-Barros, Shyam Rao, Jimmy A. Rotolo, Chris Thompson, Aviram Mizrachi, Regina Feldman, Katia Manova, Alicja Bielawska, Jacek Bielawska, Zvi Fuks, Richard Kolesnick, Adriana Haimovitz-Friedman

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)52-61
Number of pages10
JournalCellular Signalling
Volume29
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Targeting acid sphingomyelinase with anti-angiogenic chemotherapy'. Together they form a unique fingerprint.

  • Cite this

    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. (2017). Targeting acid sphingomyelinase with anti-angiogenic chemotherapy. Cellular Signalling, 29, 52-61. https://doi.org/10.1016/j.cellsig.2016.09.010