title: PPARα activation can help prevent and treat non-small cell lung cancer.
abstract: Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of proangiogenic epoxyeicosatrienoic acids (EET) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans.
authors.affiliation: Authors' Affiliations: Departments of Medicine, Division of Nephrology, Cancer Biology, and Biochemistry, Vanderbilt University; Department of Medicine, Veterans Affairs Hospital, Nashville, Tennessee; and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Skrypnyk
authors.forename: Xiwu
authors.initials: X
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.forename: Stacey
authors.initials: S
authors.lastname: Mont
authors.forename: Shilin
authors.initials: S
authors.lastname: Yang
authors.forename: Mahesha
authors.initials: M
authors.lastname: Gangadhariah
authors.forename: Shouzuo
authors.initials: S
authors.lastname: Wei
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Jawahar Lal
authors.initials: JL
authors.lastname: Jat
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001629:Bezafibrate / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D042783:Endothelial Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D047493:PPAR alpha / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D003577:Cytochrome P-450 Enzyme System; C492667:Cyp2c23 protein, mouse; D000072467:Cytochrome P450 Family 2; D001629:Bezafibrate