Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment

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Prostaglandins and Other Lipid Mediators

Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment

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Karin Larsson, Per-Johan Jakobsson ∗ Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden

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Article history: Received 30 January 2015 Received in revised form 22 May 2015 Accepted 2 June 2015 Available online xxx

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The bioactive lipid prostaglandin E2 (PGE2 ) is involved in several steps of carcinogenesis in some of the most common cancers, e.g. colon cancer, lung cancer, prostate cancer and breast cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) that target cyclooxygenase (COX) activity, the first step of the PGE2 biosynthesis, has been found to reduce the incidence of colon cancer. Due to severe adverse effects on the gastrointestinal tract and the cardiovascular system, their use as chemopreventing agent has been hampered. Genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme responsible for the second step of the PGE2 biosynthesis, has resulted in reduced tumor progression in mouse models of colon cancer. Inhibition of mPGES-1 would potentially be beneficial to a great number of patients without the side effects associated with long-term treatment with traditional NSAIDs. © 2015 Published by Elsevier Inc.

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Keywords: Prostaglandin E2 Microsomal prostaglandin E synthase-1 Targeted therapy Cancer treatment

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1. Introduction

2. Prostaglandin E2 biosynthesis

Prostaglandin E2 (PGE2 ) is a biologically active lipid involved in many physiological processes, e.g. smooth muscle contraction and blood pressure as well as in pathological conditions such as autoimmune diseases [1]. Prostaglandin E2 has also been implicated in various tumor types including colon [1–3], prostate [4,5], lung [6] and breast cancer [7]. PGE2 is formed from arachidonic acid via a reactive intermediate, prostaglandin H2 (PGH2 ). The first catalytic step is performed by cyclooxygenases (COX)-1 or COX-2 and the second step by a PGE synthase. Epidemiologic studies have found that use of non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit either COX-1, COX-2 or both have a protective effect against cancer [8]. Since inflammation was included as one of the hallmarks of cancer [9], the actions of PGE2 has been coupled to several steps of tumorigenesis, i.e. increased proliferation of tumor cells [10,11], resistance to apoptosis [12], increased invasiveness and metastasis [13], angiogenesis [14,15] and immunosuppression [16,17]. Considering the various steps of tumorigenesis affected by PGE2 , therapies targeting this lipid mediator could be beneficial to a vide array of cancer patients.

Arachidonic acid is released from fatty acids in cellular membranes by phospholipase A2 (PLA2 ) and converted into prostaglandin (PG) H2 by one of the two cyclooxygenases COX-1 or COX-2. The reactive intermediate molecule PGH2 is then further processed into five bioactive lipids, i.e. PGE2 , PGD2 , PGF2␣ , PGI2 (prostacyclin) and TxA2 (thromboxane) by specific terminal enzymes. PGE2 is converted from PGH2 by microsomal prostaglandin E synthase 1 (mPGES-1). PGE2 is subsequently released from the cell and able to confer autocrine or paracrine downstream signaling via four G-protein coupled receptors, EP1–EP4. The biosynthesis of prostanoids (prostaglandins and thromboxane) is summarized in Fig. 1. The terminal enzyme responsible for PGE2 formation, mPGES1, is an integral membrane protein in the Membrane-Associated protein in Eicosanoid and Glutathione metabolism (MAPEG) superfamily [18]. Three units of mPGES-1 form the active enzyme, which is dependent on glutathione (GSH) for its catalytic activity. The lipid substrate PGH2 binds together with GSH between transmembrane region one and four in neighboring subunits [19]. In normal conditions mPGES-1 is expressed at low levels but upon pro-inflammatory stimuli, endotoxins and growth factors, e.g. interleukin-1␤ (IL-1␤) [20], lipopolysaccharide (LPS) [21] and epidermal growth factor (EGF) [22], the enzyme is quickly induced. There are also two other reported PGE2 synthases, microsomal prostaglandin E synthase 2 (mPGES-2) and cytosolic prostaglandin

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∗ Corresponding author. Tel.: +46 0 8 517 711 85. E-mail address: [email protected] (P.-J. Jakobsson). http://dx.doi.org/10.1016/j.prostaglandins.2015.06.002 1098-8823/© 2015 Published by Elsevier Inc.

Please cite this article in press as: Larsson K, Jakobsson P-J. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins Other Lipid Mediat (2015), http://dx.doi.org/10.1016/j.prostaglandins.2015.06.002

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Fig. 1. Schematic overview of the COX pathway and points of inhibition. Arachidonic acid is converted by cyclooxygenases (COX) to a reactive intermediate PGH2 . Terminal synthases further converts PGH2 into prostaglandins and thromboxane. The bioactive lipids then confer their function via respective receptor(s): EP1–EP4 = prostaglandin E2 (PGE2 ) receptors; DP1, DP2 = prostaglandin D2 (PGD2 ) receptors; IP = prostacyclin (PGI2 ) receptor; TP = thromboxane (TXA2 ) receptor and FP = prostaglandin F2␣ (PGF2␣ ) receptor. To inhibit PGE2 biosynthesis either COX or mPGES-1 can be targeted.

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E synthase (cPGES), structurally distinct from mPGES-1 [23,24]. However, their in vivo contribution to PGE2 biosynthesis remains unclear [25,26]. cPGES (also known as p23 or cPGES/p23) has been shown to promote cancer progression as a co-chaperone to Hsp90, but not associated to PGE2 synthase activity [27,28]. 3. PGE2 inhibition in cancer Non-steroidal anti-inflammatory drugs (NSAIDs) target COX-1 and COX-2, thus act by inhibiting the conversion of arachidonic acid to PGH2 , the first step in the prostanoid synthesis. NSAIDs are used to treat inflammation and pain and they range from COX-1 selective (aspirin, naproxen) to COX-2 selective (celecoxib, rofecoxib) with most NSAIDs inhibiting both enzymes to a varying extent, so called non-selective (ibuprofen, diclofenac). Besides pain and inflammation management, several epidemiologic studies have demonstrated reduced incidence of cancer with regular use of NSAIDs [8,29]. In a meta-analysis of more than 30 epidemiological studies, a decreased risk of cancer in the colon (43%), breast (25%), lung (28%), and prostate (27%) was seen with regular intake of NSAIDs, primarily aspirin and ibuprofen [8]. Most epidemiological studies so far have investigated COX inhibition as chemopreventive treatment. However, in a recent study, patients with stage III colon cancer that were enrolled in an adjuvant chemotherapy trial showed both significantly increased ‘event free’ and ‘overall’ survival after consistent use of aspirin or COX-2 selective drugs (celecoxib or rofecoxib) during and after chemotherapy (according to questionnaires) [30]. In addition to COX enzyme inhibition, there are also molecules that inhibit COX-2 expression. Both pharmacologic inhibition and genetic deletion of 11␤-hydroxysteroid dehydrogenase type II decreased expression of COX-2 (and PGE2 ) resulting in suppression of colon carcinogenesis in mice, without affecting prostacyclin levels [31,32]. Due to the adverse effects of long term COX inhibition, caused by general inhibition of all prostanoids important for normal cellular functions, with predominantly gastrointestinal tract [33] and cardiovascular adverse effects [34–36] these findings have not led to any general recommendation to prescribe NSAIDs as chemopreventive drugs. Attempts have been made to resolve the gastrointestinal problems associated with COX-1 selective NSAIDs,

by developing COX-2 selective drugs (Coxibs), e.g. rofecoxib and celecoxib. Promising results was seen in clinical trials [37–39], but due to unforeseen serious cardiovascular side effects, possibly due to a shift in the thromboxane/prostacyclin balance, the use of selective COX-2 inhibitors has been hampered. Interestingly, in a recent publication, an alternative mechanism for the cardiovascular side effects of COX-2 inhibition has been proposed [40]. Inhibition of renal COX-2 leads to an increase in asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, and therefore a decrease in vasculature protective nitric oxide. Thus, there are both advantages and disadvantages associated with the use of NSAIDs as chemoprevention. COX-1 selective NSAIDs act chemoprotective and aspirin also have cardioprotective effects [41]. On the other hand, long-term use causes gastrointestinal problems and bleedings. COX-2 selective NSAIDs have promising anti-tumorigenic effects both as preventive agent and as adjuvant treatment but many epidemiologic studies have shown serious cardiovascular side effect of these drugs. Targeting mPGES1, the downstream enzyme responsible for PGE2 synthesis would hopefully retain the anti-tumorigenic properties of COX inhibition without the adverse side effects. 4. Genetic deletion of mPGES-1 Genetic deletion of mPGES-1 in mouse models has showed that inhibition of PGE2 formation is a possible future targeted cancer treatment. Nakanishi et al. showed that Apc-mutant mice with a genetic deletion of mPGES-1 had a 66% decrease of intestinal cancer growth and 95% reduction in large adenomas [42]. mPGES-1 knockout (KO) mice were also protected against azoxymethane (AOM)-induced colon cancer with reduced number of aberrant crypt foci and up to 90% decrease in tumor load in the distal colon [43]. Genetic deletion of mPGES-1 in a HER2 receptor driven breast cancer mouse model also showed reduced number of larger tumors, in addition to suppression of angiogenesis in mammary glands [44]. In a study using xenografts from prostate cancer cells (RM9) Takahashi et al. showed that the number of lung metastases and tumor load in the lung was reduced in mice treated with celecoxib. The same effect was obtained in mPGES-1 KO mice. The reduction in lung metastases was also coupled to a decrease in angiogenesis in the lung tissue [45]. There are also mice models with cell specific KO

Please cite this article in press as: Larsson K, Jakobsson P-J. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins Other Lipid Mediat (2015), http://dx.doi.org/10.1016/j.prostaglandins.2015.06.002

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Fig. 2. Overview of mPGES-1 protein structure. mPGES-1 is composed of four transmembrane (TM) regions connected by flexible loops. Three amino acids in the active site of mPGES-1, situated in TM4 are not conserved between human (red) and rat/mouse (green) enzyme. These phylogenetic differences results in a more restricted catalytic cleft in the rodent enzyme, rendering most inhibitors developed for the human enzyme inefficient toward rat/mouse mPGES-1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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of mPGES-1 in endothelial cells, vascular smooth muscle cells and myeloid cells [46] opposed to somatic KO of mPGES-1 (that were used in the models mentioned above). These cell specific KO mice have so far not been combined with any tumor models. They will nonetheless be of great value to establish possible effect of PGE2 on the cardiovascular system. Other types of models with cell/tissue specific mPGES-1 KO are xenograft models using mPGES-1 deleted tumor cells. In these models, the tumor cells lack PGE2 production but the host cells have normal production of PGE2 . We have previously shown that the tumor growth in mice xenografts using a lung cancer cell line (A549) and a prostate cancer cell line (DU145) with mPGES-1 knockdown was considerably slowed compared to cells with endogenous mPGES-1 expression [4]. Taken together, these results suggest that direct targeting of mPGES-1 is a promising strategy for targeted cancer therapy, thereby circumventing the disadvantageous effects of COX inhibition. 5. mPGES-1 inhibitors in cancer Pharmacological inhibition of mPGES-1 has successfully been demonstrated in preclinical models of inflammation [47–50]. Notwithstanding the important role for mPGES-1 and PGE2 in tumorigenesis, there are not many in vivo studies on the effect of pharmacological mPGES-1 inhibition as cancer treatment. This probably results from the phenotypic differences between human and murine enzymes, which have hampered research on the effects of mPGES-1 inhibition in cancer. Three amino acids in the active site of mPGES-1 are not conserved between human and rat/mouse enzyme [51] (Fig. 2). Two additional amino acids outside of the active site have also been proposed to contribute to the human/murine inhibitor binding differences in a study based on high-resolution crystal structure analysis [52]. These differences have rendered most inhibitors efficient to the human enzyme e.g. MF63 and PF-9184 inefficient to the murine enzyme [47,48], hence hindering studies in common mouse tumor models. This obstacle was overcome by using human xenografts in nude mice in a study by Finetti et al. [53]. A carbazole benzamide derivative, AF3485 that inhibits human mPGES-1 in the low micro molar range, with no inhibition of other related MAPEG proteins or rodent mPGES-1 was used. The inhibitor both reduced growth of A431 cells in vitro, and reduced tumor growth in mice bearing A431 xenograft in vivo. In the xenograft model, treatment with AF3485 also reduced phosphorylation of epidermal growth factor receptor (EGFR) and a significant reduction of vascularization was observed in tumors from treated mice compared to vehicle treated mice [53]. In another study, Chang et al. identified PGE0001 in an in silico screen of a small compound library. PGE0001 reduced PGE2 production in vitro and xenograft lung and colorectal cancer mouse models revealed an anti-tumor effect in vivo. The small molecule was found to bind to human mPGES-1 but no in vitro inhibition could be detected, thus the mechanism behind PGE2 reduction remains unclear [54].

In vitro studies of pharmacological inhibition of mPGES-1 have demonstrated anti-tumorigenic effects in cancer cells. Beales and Ogunwobi showed reduced proliferation and increased apoptosis in esophageal adenocarcinoma cells treated with CAY10526. The same compound did not affect prostacyclin levels in epithelial cells, which was completely abolished by COX-2 inhibitors [55]. The mPGES-1 inhibitor MK886 (also a FLAP inhibitor) was found to reduce proliferation of leukemia cells by inducing apoptosis [56]. Lately, there is emerging evidence that stromal cells like fibroblasts and macrophages contribute substantially to PGE2 production in tumors leading to an enhanced proliferation and invasiveness of tumor cells [57–59]. In xenograft mouse models, mPGES-1 expressed by macrophages and fibroblasts are of murine origin and mPGES-1 expressed by tumor cells are of human origin. Therefore, selective human mPGES-1 inhibitors are likely to show less potency in xenograft mouse models in which the cancer cells are not the only source of mPGES-1. Recently, we described a dual rat/human mPGES-1 inhibitor, compound II, effective both in cell-free assays, and in cellular in vitro assays as well as in vivo models of inflammation. The inhibitor also suppressed PGE2 production in A549 cells [49]. We have also characterized another mPGES-1 inhibitor, compound III [60] that we found to have both in vitro and in vivo effects in mouse peritoneal macrophages and in rat models of inflammation as well as in human whole blood assays [60]. The in vivo anti-tumor effect of these dual inhibitors is currently under investigation by us and others. When inhibiting synthesis of PGE2 , a build-up of PGH2 might lead to a shunting effect, i.e. an increased production of other prostanoids. There are indications that genetic deletion of mPGES-1 leads to redirection of PGH2 conversion from PGE2 to TXB2 (thromboxane metabolite), indicating a risk of cardiovascular side effects. Montrose et al. showed that the production of TXB2 and PGD2 was increased as an effect of decreased PGE2 production in the colon of mPGES-1 KO mice [61]. We have also seen the same redirection from PGE2 to TXB2 in both peritoneal macrophages and in air pouch exudate of mPGES-1 KO mice [60]. On the contrary, peritoneal macrophages from wild type mice treated with compound III instead had a shunting to 6-keto PGF1␣ (prostacyclin metabolite). The prostanoids profile of the air pouch exudate was unchanged except for a decrease in PGE2 upon treatment with compound III [60]. Beales et al. showed that the production of prostacyclin in endothelial cells was unaffected by treatment with the mPGES-1 inhibitor CAY10526 [55]. In another study, pharmacological inhibition of mPGES-1 with MF63 in A549 cells resulted in increased levels of PGF2␣ whereas TXB2 levels remained unchanged [48]. 6. Conclusions and future perspectives Even though prostaglandin E2 has been assigned an important role for development and progression of cancer, NSAIDs are not routinely used in the clinic as treatment of cancer patients or as

Please cite this article in press as: Larsson K, Jakobsson P-J. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins Other Lipid Mediat (2015), http://dx.doi.org/10.1016/j.prostaglandins.2015.06.002

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chemopreventive treatment, due to adverse side effects caused by the general inhibition of prostaglandins important for normal cellular processes. Genetic deletion of mPGES-1 has successfully demonstrated selective inhibition of PGE2 as a possible way to avoid general and detrimental down regulation of prostaglandins resulting from COX inhibition, but there is no selective mPGES1 inhibitors on the market. What remains to be done in order to get mPGES-1 inhibitors out to the clinics as treatment for cancer patients? First, more animal studies need to be done both to establish a robust anti-tumor effect as well as to rule out toxic side effects. Second, possible shunting to other prostanoids needs to be investigated thoroughly. Pharmacological inhibition of mPGES-1 also needs to be carefully compared to COX-1 and COX-2 selective inhibitors both in terms of anti-tumor efficiency and side effects. To date, most studies of the role of PGE2 and the effect of mPGES-1 inhibition are investigated in epithelial cancers. We have previously investigated the role of prostanoids in mouse models of neuroblastoma, a neuroendocrine embryonic tumor and found a significant reduction in tumor volume upon low-dose aspirin treatment compared to diclofenac treated or untreated [62], suggesting an involvement of COX-1. The involvement of mPGES-1 and PGE2 still needs to be elucidated in this model. Inhibition of mPGES1 could possibly then also be effective in tumors lacking COX-2 expression. Even though mPGES-1 inhibitors could be suitable as future adjuvant treatment in a broad array of cancer patients this should be determined case-by-case depending on expression of COX-1, COX-2 and mPGES-1. There are promising results from selective mPGES-1 inhibitors in preclinical models of inflammation but only a few studies in animal models due to phenotypic differences between the murine and human enzyme. Recent progress in the field has generated inhibitors active against both human and murine enzymes. These inhibitors are valuable tools for further studies of the role of mPGES1 in experimental models of cancer and cardiovascular toxicity and the in vivo effects are anticipated with great interest.

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Acknowledgements

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This study was supported by The Swedish Childhood Cancer Q4 Foundation, The Swedish Research Council, The Swedish Rheuma279 tism Association, King Gustaf V 80 years Foundation, Karolinska 280 Institutet Foundation and The Stockholm County Council. 281 Q3 278

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Please cite this article in press as: Larsson K, Jakobsson P-J. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. Prostaglandins Other Lipid Mediat (2015), http://dx.doi.org/10.1016/j.prostaglandins.2015.06.002

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