Introduction: The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple central nervous system tumor cell types.
Methods: Flow sorting,real time cell viability assays and immunohistochemical staining techniques were used to determine cell viability and activity in the present of drug treatment. Primary isolates of human glioblastoma cells and associated microglia were obtained and treated in vivo. A nude mouse model of GBM growth in the flank was employed to further investigate in vivo findings.
Results: Celecoxib and sildenafil killed ex vivo primary human glioblastoma and medulloblastoma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1a/XBP1 enhanced killing whereas knock down of eIF2a/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of central nervous system tumors in vivo.
Conclusions: Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.
Patient Care: This research identifies a potential novel drug combination therapy that is easily accessible and cost effective for the treatment of CNS malignancies.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of PDE5 enhancement in the Celecoxib killing of CNS tumors 2) Discuss the molecular mechanisms involved in their interaction and lethality, 3) Identify drug combination of Celecoxib and PDE5 inhibitors as a cost effective, easily accessible treatment of aggressive CNS malignancies.