TY - JOUR
T1 - Targeting acid sphingomyelinase with anti-angiogenic chemotherapy
AU - Jacobi, Jeanna
AU - García-Barros, Mónica
AU - Rao, Shyam
AU - Rotolo, Jimmy A.
AU - Thompson, Chris
AU - Mizrachi, Aviram
AU - Feldman, Regina
AU - Manova, Katia
AU - Bielawska, Alicja
AU - Bielawska, Jacek
AU - Fuks, Zvi
AU - Kolesnick, Richard
AU - Haimovitz-Friedman, Adriana
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Acid sphingomyelinase
KW - Anti-angiogenic drugs
KW - Ceramide-rich macrodomains
KW - Chemotherapy
KW - Endothelial cells
UR - http://www.scopus.com/inward/record.url?scp=84993929167&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84993929167&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2016.09.010
DO - 10.1016/j.cellsig.2016.09.010
M3 - Article
C2 - 27702691
AN - SCOPUS:84993929167
VL - 29
SP - 52
EP - 61
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
ER -