Inhibition of thromboxane synthase activity improves glioblastoma response to alkylation chemotherapy.
Thromboxane synthase (TXSA), an enzyme of the arachidonic acid metabolism, is upregulated in human glial tumors and is involved in glioma progression. Here, we analyzed the in vitro and in vivo effects of pharmacological inhibition of TXSA activity on human glioblastoma cells. Furegrelate, a specific inhibitor of TXSA, significantly inhibited tumor growth in an orthotopic glioblastoma model by inducing proapoptotic, antiproliferative, and antiangiogenic effects. Inhibition of TXSA induced a proapoptotic disposition of glioma cells and increased the sensitivity to the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea, significantly prolonging the survival time of intracerebral glioma-bearing mice. Our data demonstrate that the targeted inhibition of TXSA activity improves the efficiency of conventional alkylation chemotherapy in vivo. Our study supports the role of TXSA activity for the progression of malignant glioma and the potential utility of its therapeutic modulation for glioma treatment.
Schmidt
Nils Ole
NO
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ziu
Mateo
M
Cargioli
Theresa
T
Westphal
Manfred
M
Giese
Alf
A
Black
Peter M
PM
Carroll
Rona S
RS