title: PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib].
abstract: The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1. Enhanced cell killing by sildenafil was blocked by inhibition of death receptor signaling and autophagosome formation. Enforced activation of STAT3 and AKT or inhibition of JNK significantly reduced cell killing. The enhanced cell killing caused by sildenafil was more reliant on increased PKG signaling than on the generation of nitric oxide. In vivo sildenafil enhanced the anti-tumor properties of [pemetrexed + sorafenib]. Based on our data we argue that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted.
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Booth
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Roberts
authors.affiliation: Department of Biochemistry and Medicine, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.affiliation: Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068437:Pemetrexed / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D010671:Phenylurea Compounds; D058986:Phosphodiesterase 5 Inhibitors; D000068437:Pemetrexed; D009536:Niacinamide; D000077157:Sorafenib; D000068677:Sildenafil Citrate
keywords: autophagy; chaperone; lung cancer; pemetrexed; sildenafil