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 pro-angiogenic epoxyeicosatrienoic acids (EETs) 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.

The prostaglandin and leukotriene families of lipid mediators are formed via two distinct biosynthetic pathways that are initiated by the oxygenation of arachidonic acid by either cyclooxygenase-2 (COX-2) or 5-lipoxygenase (5-LOX), respectively. The 5-LOX product 5S-hydroxyeicosatetraenoic acid, however, can also serve as an efficient substrate for COX-2, forming a bicyclic diendoperoxide with structural similarities to the arachidonic acid-derived prostaglandin endoperoxide PGH 2 [Schneider C, et al. (2006) J Am Chem Soc 128:720-721]. Here we identify two cyclic hemiketal (HK) eicosanoids, HKD 2 and HKE 2 , as the major nonenzymatic rearrangement products of the diendoperoxide using liquid chromatography-mass spectrometry analyses as well as UV and NMR spectroscopy. HKD 2 and HKE 2 are furoketals formed by spontaneous cyclization of their respective 8,9-dioxo-5S,11R,12S,15S-tetrahydroxy-or 11,12-dioxo-5S,8S,9S,15S-tetrahydroxy-eicosadi-6E,13E-enoic acid precursors, resulting from opening of the 9S,11R-and 8S,12S-peroxide rings of the diendoperoxide. Furthermore, the diendoperoxide is an efficient substrate for the hematopoietic type of prostaglandin D synthase resulting in formation of HKD 2 , equivalent to the enzymatic transformation of PGH 2 to PGD 2 . HKD 2 and HKE 2 were formed in human blood leukocytes activated with bacterial lipopolysaccharide and calcium ionophore A23187, and biosynthesis was blocked by inhibitors of 5-LOX or COX-2. HKD 2 and HKE 2 stimulated migration and tubulogenesis of microvascular endothelial cells, implicating a proangiogenic role of the hemiketals in inflammatory sites that involve expression of 5-LOX and COX-2. Identification of the highly oxygenated hemiketal eicosanoids provides evidence for a previously unrecognized biosynthetic cross-over of the 5-LOX and COX-2 pathways.L eukotrienes and prostaglandins are lipid mediators derived from oxidative modification of arachidonic acid. Both families of eicosanoids exert inflammatory and immunomodulatory functions in disease, as well as homeostatic functions in normal physiological processes (1). Atherosclerosis, asthma, and many types of cancer are prototypical inflammatory diseases that are characterized by concomitant formation of both leukotrienes and prostaglandins (2). The formation of leukotrienes and prostaglandins diverges at the point of the initial oxygenation of the common arachidonic acid substrate by either 5-lipoxygenase (5-LOX) or cyclooxygenase-2 (COX-2), respectively. From there, biosynthesis proceeds along separate and distinct pathways, each utilizing specific enzymes that catalyze complex reactions using highly unstable substrates (3, 4).The possibility of a biosynthetic convergence of the 5-LOX and COX-2 pathways was implicated when the 5-LOX product 5S-hydroxyeicosatetraenoic acid (5S-HETE) was identified as an efficient and specific substrate for oxygenation by recombinant COX-2 (5). The COX-2 oxygenation product of 5S-HETE is a bicyclic diendoperoxide with structural similarities to the prostaglandin (PG) e...

Highlights d Breast cancer cells treated with CDK4/6 inhibitor secrete chemokines CCL5 and CXCL10 d Chemokine induction is associated with deregulated mTOR, metabolic stress, and ROS d Chemokines induced by CDK4/6 inhibitor facilitate T cell infiltration into tumors d Chemokines induced by CDK4/6 inhibitor augment adoptive T cell therapy