Suppressed proteasomal degradation of HIF-1 and increased HIF-1 transcriptional activity occurs when HIF prolyl hydroxylase activity is usually inhibited by proline. inhibition of COX-1 evokes antiplatelet effect, inhibition of COX-2 has strong anti-inflammatory, antipyretic and analgesic effects [2, 3]. It is well established that inflammatory environment promotes cancer development. The mechanism of this process is due to increased levels of COX-2 and prostaglandin E2 (PGE2) [4C7] that promote proliferation, migration, invasion, and cell adhesion [8, 9]. According to these facts, medication with NSAIDs was associated with decreased risk of certain cancer types, particularly gastrointestinal tract cancers (gastric or colorectal cancer), lung, breast, and prostate cancers [10C14]. Clinical and pharmacoepidemiological studies provide evidence that aspirin and other cyclooxygenase-2 enzyme inhibitors lower recurrence of colorectal cancer by about 20% [12, 15, 16]. Another example is usually that regular, non-selective COX-2 NSAIDs treatment (i.e. aspirin and ibuprofen) caused a 69% reduction in the relative risk of lung cancer [17]. The explanation for the potential mechanism of anticancer activity of NSAIDs comes from studies around the inhibitory effect on cyclooxygenases that are frequently overexpressed in different types of cancer [18, 19]. Such a mechanism was observed in cultured HT-29 human colon cancer cells where apoptosis occurred after incubation with sulindac and sulindac sulfide, salicylate and other NSAIDs [20]. COX-2 inhibition attenuates also angiogenesis through expression of vascular endothelial growth factor (VEGF) and metalloproteinases [21]. However, some experiments show that this anti-neoplastic effect of NSAIDs is usually more complex and cannot be explained on the basis of cyclooxygenase inhibition pathway [22]. In human prostate cancer cell lines, PC3 and LNCaP which are lacking COX-2, the treatment with selective COX-2 inhibitor, celecoxib inhibited the growth of both cell lines independently of PGE2 level. The similar effect was observed in vivo [23, 24]. Other representative studies carried out using human colon cancer HT-29 cells expressing COX-1 and -2 and HCT-15 lacking both isoforms of cyclooxygenase confirmed prostaglandin-independent effects of NSAIDs. However, the concentrations of NSAIDs required for inhibition of COX and cancer cell proliferation are different [20, 25]. BGB-102 The concentration of NSAIDs required for inhibition of cell proliferation is much higher than those for inhibition of cyclooxygenases activity. Another evidence for COX-independent effect of NSAIDs was provided by studies on chiral centers of ibuprofen and flurbiprofen. When the drugs are em S /em -enantiomers they evoke non-selective COX inhibition while em R /em -enantiomers are deprived of both COX-1 or COX-2 inhibitory activity. However, both em S /em – and em R /em -enantiomers have the same anti-proliferative effects. It has been suggested that this effects of NSAIDs can be related to inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP PDEs) signaling, Wnt/-catenin signaling, peroxisome proliferator-activated receptors, retinoid X receptors, IKK/NF-B, PDK-1/AKT, Akt/mTOR signaling inhibition and AMP-activated protein kinase (AMPK) up-regulation [26C28]. Another possible pathway potentially involved in NSAIDs induced apoptosis in cancer cells is related to the activity of 15-lipoxygenase-1 (15-LOX-1). COX and LOX are the major enzymes responsible for polyunsaturated fatty acids metabolism. In vitro and in vivo studies indicated that gene expression of 15-LOX-1 and level of its main product, 13-hydroxyoctadecadienoic acid (13-S-HODE) is usually significantly decreased BGB-102 in adenomas or carcinomas comparing to normal mucosa [29, 30]. LOX is the main enzyme metabolizing colonic linoleic acid to eicosanoids. In-vitro experiments with colon cancer cells that have a different level of COXs expression show that NSAIDs (e.g. sulindac sulfone) can up-regulate 15-LOX-1 expression and increase the formation of 13-S-HODEthe main metabolic product of this enzyme. These effects were related to the apoptosis induction in colon cancer cells and LOX-dependent apoptosis was reversed by using caffeic acida 15-LOX-1 inhibitor. When the cells had been incubated with sulindac sulfone Oddly enough, caffeic acidity PGR and 13-S-HODE, apoptosis was considerably elevated however the substitution of 13-S-HODE by linoleic acidity had no impact in this mixture. One explanation of the effect could be a change of substrate from the COXs and toward the LOXs [31]. Another probability may be the discussion between LOX activity and peroxisome proliferator-activated receptors (PPARs). Improved degree of BGB-102 13-S-HODE, in response to 15-LOX-1 activation could be in charge of significant down-regulation of peroxisome proliferator-activated receptor (PPAR) in RKO and DLD-1 cancer of the colon cells. Linoleic acidity like a substrate for 15-LOX-1 didn’t possess the same impact alone. Further tests demonstrated that molecular system for this results is also linked to 13-S-HODE immediate binding with PPAR and downregulation of its manifestation [32,.