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 1-2h 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.
authors.affiliation: Department of Radiation Oncology, USA.
authors.forename: Jeanna
authors.initials: J
authors.lastname: Jacobi
authors.affiliation: Laboratory of Signal Transduction, USA.
authors.forename: Mónica
authors.initials: M
authors.lastname: García-Barros
authors.affiliation: Department of Radiation Oncology, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Rao
authors.affiliation: Laboratory of Signal Transduction, USA.
authors.forename: Jimmy A
authors.initials: JA
authors.lastname: Rotolo
authors.affiliation: Department of Radiation Oncology, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Thompson
authors.affiliation: Head and Neck Service, Department of Surgery, USA.
authors.forename: Aviram
authors.initials: A
authors.lastname: Mizrachi
authors.affiliation: Department of Radiation Oncology, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Feldman
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawska
authors.affiliation: Department of Radiation Oncology, USA.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fuks
authors.affiliation: Laboratory of Signal Transduction, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
authors.affiliation: Department of Radiation Oncology, USA. Electronic address: a-haimovitz-friedman@ski.mskcc.org.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002518:Ceramides / Q000378:metabolism; D016503:Drug Delivery Systems; D004727:Endothelium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D017239:Paclitaxel / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002518:Ceramides; D013108:Sphingomyelin Phosphodiesterase; D017239:Paclitaxel
keywords: Acid sphingomyelinase; Anti-angiogenic drugs; Ceramide-rich macrodomains; Chemotherapy; Endothelial cells