title: PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells.
abstract: We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.
authors.affiliation: Department of Biochemistry; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Conley
authors.affiliation: Department of Biochemistry; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.affiliation: Department of Neurology; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Malkin
authors.affiliation: Department of Cardiology; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.affiliation: Department of Medicine; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.affiliation: Department of Medicine; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: Department of Biochemistry; Virginia Commonwealth University; Richmond, VA USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014750:Vincristine; D005047:Etoposide; D000068677:Sildenafil Citrate; D002945:Cisplatin
keywords: PDE5; chemotherapy; medulloblastoma; pediatric; sildenafil