Topics in Anti-Cancer Research: Volume 6 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Topics in Anti-Cancer Research
- Sprache: Englisch
Topics in Anti-Cancer Research covers important advances on both experimental (preclinical) and clinical cancer research in drug development. The book series offers readers an insight into current and future therapeutic approaches for the prevention of different types of cancers, synthesizing new anti-cancer agents, new patented compounds, targets and agents for cancer therapy as well as recent molecular and gene therapy research.
The comprehensive range of themes covered in each volume will be beneficial to clinicians, immunologists, and R&D experts looking for new anti-cancer targets and patents for the treatment of neoplasms, as well as varied approaches for cancer therapy.
The topics covered in the sixth volume of this series include:
- The role of microtubules for the cure of various untreated cancers
- Novel chemoimmunotherapy drug combinations & methods in clinical studies/trials
- Targeting polyunsaturated fatty acids (PUFAs) in the treatment of colorectal cancer
- Anti-cancer activity of natural and synthetic chalcones and their derivatives
- Recent advances in microRNA-based cancer therapeutics
- The role of inflammation in chemotherapy-induced neuromuscular effects
- Recent patents for treating heart failure due to inflammation, mitochondria and energy metabolism in cancer cachexia
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Veröffentlichungsjahr: 2017
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“Topics in Anti-Cancer Research”
Volume 6
Atta-ur-Rahman,FRS
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Khurshid Zaman
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INTRODUCTION
Topics in Anti-Cancer Research covers important advances on both experimental (preclinical) and clinical cancer research in drug development. The book series offers readers an insight into current and future therapeutic approaches for the prevention of different types of cancers, synthesizing new anti-cancer agents, new patented compounds, targets and agents for cancer therapy as well as recent molecular and gene therapy research.
The comprehensive range of themes covered in each volume will be beneficial to clinicians, immunologists, and R&D experts looking for new anti-cancer targets and patents for the treatment of neoplasms, as well as varied approaches for cancer therapy.
The topics covered in the sixth volume of this series include:
- The role of microtubules for the cure of various untreated cancers - Novel chemoimmunotherapeutic drug combinations & methods in clinical studies/trials - Targeting polyunsaturated fatty acids (PUFAs) in the treatment of colorectal cancer - Anti-cancer activity of natural and synthetic chalcones and their derivatives - Recent advances in microRNA-based cancer therapeutics - Treatment of heart failure due to inflammation, mitochondria and energy metabolism in cancer cachexia - Regulation/inhibition of human lactate dehydrogenase A for discovering anti-cancer drugs
FOREWORD
The sixth volume of Topics in Anti-Cancer Research presents some exciting contributions in frontier areas of anti-cancer research. These include the role of microtubules for the treatment of various cancers, novel chemoimmunotherapy drug combinations & methods in clinical studies/trial and current studies in targeting polyunsaturated fatty acids (PUFAs) in the treatment of colorectal cancer. Natural and synthetic chalcones and their derivatives that have shown potent anticancer activity against a number of cancer cell lines and murine tumor models are discussed. The discovery of selective small-molecule hLDH-A inhibitors and LDH-based approaches in the progress of anticancer therapy are also presented. Recent advances in microRNA-based cancer therapeutics for the treatment of cancer are presented. The role of inflammation in chemotherapy-induced neuromuscular effects and the side effects and recent relevant patents for beneficial approaches to improve heart failure cases due to inflammation, mitochondria and energy metabolism in cancer cachexia are also covered. It is hoped that the present volume will be found useful by a large number of scientists working in this field.
The editors are thankful to the authors for their excellent contributions and to the reviewers for their in -depth comprehensive comments for the improvement of chapters. We are also grateful to Mr. Mahmood Alam, Mrs. Rafia Rehan and other colleagues for their support and assistance in the finalization of this volume.
List of Contributors
Targeting Polyunsaturated Fatty Acid Metabolism in Colorectal Cancer Therapy: A Review of Recent Patents
Arkadiusz Michalak#,Paula Mosińska*,#,Jakub FichnaAbstract
In the recent years, fatty acids (FAs) have been acknowledged not only as building materials for lipid membranes and carbon source for β-oxidation, but also as important signaling molecules. In this field, polyunsaturated fatty acids (PUFAs) have received special attention as modulators of inflammation. The enzymes that process PUFAs into bioactive metabolites (cyclooxygenases, lipoxygenases) have already been targeted by pharmaceutical agents. Given the fact that intense synthesis of FAs is a metabolic hallmark of cancer, it is expected that FAs play an important role in cancer development, progression and invasion, and could be targeted by modern therapies. In this chapter, we will discuss the possible use of FAs and drugs affecting their metabolism against colorectal cancer (CRC), which is strongly associated with environmental factors such as high-fat, high caloric diet and obesity. We will cover the role of n-3 PUFAs as dietary supplements in primary prevention of CRC based on the results obtained from clinical trials, and elaborate on the latest patents designed to improve the bioavailability of PUFAs concentrates as nutritional treatments for patients with CRC. We will also discuss the enzymes processing PUFAs and their role in tumorigenesis with focus on their potential as markers for “molecular staging” (fatty acid synthases and elongases) and targets in therapy (cyclooxygenase 2 and lipoxygenase 5). Finally, we will examine new drug formulations (e.g. liposomes) and their utility in CRC therapy. The chapter is based on the review of literature (PubMed Database) and patent documents.
1. INTRODUCTION
Colorectal cancer (CRC) is the second most common cancer in women and third in men, responsible for 600,000 deaths annually worldwide [1-3]. It is the fourth cause of oncological deaths, which creates a substantial global burden [4]. Up to 50% of CRC risk is lifestyle-related - most prominent risk factors include obesity, sedentary behavior, alcohol consumption, tobacco smoking, high-meat / high-calorie intake, as well as fat-rich and fiber-deficient diet [5]. All of these disturb the metabolic balance and add to CRC development. A cause-effect relation has been proven for alcohol (which promotes folate deficiency and thus leads to DNA instability and carcinogenesis) and tobacco smoking (which spreads carcinogens from cigarettes to colorectal mucosa, stimulating carcinogenesis) [5]. In turn, dietary habits and sedentary lifestyle not only cause obesity but also lead to the development of metabolic syndrome highlighted by a range of abnormalities encompassing impaired glucose tolerance, elevated blood pressure and dyslipidemia. These metabolic disorders tip the cytokine balance toward chronic low-grade inflammation and further disturb the levels of adipokines e.g. adiponectin and leptin, and insulin growth factors which all affect cellular proliferation, adhesion and migration [6-8]. Moreover, unbalanced diet can directly promote carcinogenesis by modifying the intestinal microbiome and making alterations in the complexity of the colorectal mucosa - for details see [6].
Alterations in lifestyle patterns through higher intake of fish and fish oils, dietary fiber, vitamin D and calcium, regular use of aspirin and habitual physical exercise modulate the course of CRC, especially at the initial stage of its development, and improve the quality of life of patients [5]. The protective role of fish and fish oils is mainly attributed to the high content of polyunsaturated fatty acids (PUFAs). The fact that aspirin also acts on the metabolism of PUFAs further suggests that these fatty acids may play a significant role in CRC development and possible prevention.
PUFAs are organic acids comprising of a carbohydrate chain with more than one double (C=C) bond in their structure. Long-chain PUFAs are divided into n-6 PUFAs (first double bond at C6, counting from the methyl C) and n-3 PUFAs (first unsaturated bond at C3). The main representatives of these groups are linoleic acid (LA, 18:2) for n-6 PUFAs and α-linolenic acid (ALA, 18:3) for n-3 PUFAs, together called essential fatty acids (FAs). The term “essential” emphasizes their importance in maintaining the optimal health of humans and other animals, as they cannot be synthesized de novo but have to be supplemented in the diet. These FAs provide the carbon chain necessary for the synthesis of longer FAs: n-6 arachidonic acid (AA, 20:4), and n-3 eicosapentaenoic acid (EPA, 19:5) and docosahexaenoic acid (DHA, 22:6) in the reactions catalyzed by elongases and desaturases. In humans, the efficacy of transforming ALA to longer n-3 PUFAs is low and personally variable [9] and thus its derivatives should also be supplemented in diet. Animal-derived products (meat, eggs, dairy) are the most common source of LA and its derivative AA, whereas fish, particularly salmon, provides mainly n-3 PUFAs.
This chapter will briefly describe the fundamental knowledge of PUFAs and their metabolism. A detailed section is devoted to reports from the in vitro and in vivo studies investigating links between PUFAs and CRC. The main body covers various ways in which PUFAs could be utilized to prevent or treat cancer, especially CRC, based on the already established patents and promising reports from the literature.
The review is based on literature search conducted in the following databases: PubMed (for original papers and reviews), ClinicalTrials.gov, EU Clinical Trials Register and UMIM (for clinical trials), and WIPO (for pertaining to patents). The keywords used to search for patents included: adjuvant therapy, chemotherapy, colorectal cancer, dietary supplementation, docosahexaenoic acid, eicosapen-taenoic acid, endocannabinoids, fish oil, liposomes, polyunsaturated fatty acids and resolvins. The literature was searched in relation to relevant patents. Non-English articles were not included in the review. All patents and clinical trials mentioned in this paper are summarized in Tables 1 and 2, respectively.
2. PUFAS AND THEIR METABOLITES
PUFAs are important elements of cellular lipid membranes released into circulation by phospholipase A2. By undergoing various enzymatic and non-enzymatic pathways, PUFAs are converted into biologically active lipid metabolites and mediators (Fig. 1). The most prominent enzymes participating in the formation of bioactive metabolites of n-3 and n-6 PUFAs include:
Cyclooxygenases (COXs) that produce prostaglandins (PGs), thromboxanes (TXs) and prostacyclins;Lipoxygenases (LOXs) which process AA into lipoxins (LXs) and leukotrienes (LTx), and n-3 PUFA into protectins, marensins and resolvins;Cytochrome 450 (Cyp 450) which converts PUFAs into hydroxyeicosatetraenoic acids (HETEs).EPA: Eicosapentaenoic Acid; DHA: Docosahexaenoic Acid; OEA: Oleoylethanolamide
EPA: Eicosapentaenoic Acid; FFA: Free Fatty Acid; HCC: Hepatocellular Cancer; iv: Intravenous; LPS: Lipopolysaccharide; MCT/LCT: Medium/Long Chain Triglycerides; PUFAs: Polyunsaturated Fatty Acids; PVA: Polyvinyl Alcohol; RCT: Randomized Clinical Trial; TACE: Transcatether Artherial Embolisation.
PGs are a family of AA metabolites produced from a common precursor prostaglandin H2 (PGH2). Among all PGs, prostaglandin E2 (PGE2) is the most potent pro-inflammatory lipid compound secreted by macrophages and neutrophils that induce fever, increase vascular permeability, cause vasodilation and sensitize cells to other inflammatory factors, such as histamine and bradykinin. In contrast, prostaglandin D2 (PGD2) presents purely anti-inflammatory features. Other important PGs include prostaglandin F2 (PGFA2) - involved in parturition in uterus, water absorption in kidneys and vasoconstriction - and prostaglandin I2 (PGI2), which plays a role in platelet inhibition, vasodilation and regulation of renal flow.
Other AA derivatives include thromboxane A2 (TXA2), leukotriene B4 (LTB4) and LXs. The main role of TXA2 is to promote platelet aggregation and vasoconstriction. LTB4 is a pro-inflammatory chemokine which attracts neutrophils and causes vascular leakage, whereas LXs are considered pro-resolution mediators as they reduce leukocyte infiltration.
Over the last 20 years, the metabolism of FAs has been recognized as an important part of tumor biology. Human cancer cells need vast amounts of FAs to grow but instead of capturing them from the circulation they tend to synthesize them on their own. To this end, cancer cells rely on various growth factors and their receptors (EGFR, KGF, HER2) to stimulate intracellular signaling pathways (MAPKs, PI3K-AKT and JNK), and activate transcription factors (e.g. SREBP-1). This leads to overexpression of mRNA for lipogenic enzymes such as fatty acid synthase (FAS) [10]. This intensified lipid synthesis is viewed as a mechanism promoting cell survival in anaerobic environment and highlighted as a metabolic hallmark of cancer, together with intense aerobic glycolysis (known as Warburg effect) and increased protein and DNA synthesis [11]. Of note, the expression of FAS also rises in response to acidic microenvironment and boosts tumor resistance to cellular injuries caused by e.g. chemotherapy [11]. This phenomenon may be explained by the fact that FAS synthesizes mostly saturated or at most monounsaturated FAs. In effect, saturated phospholipids tend to arrange within lipid bilayer into microdomains (or “rafts”) which remain insoluble after exposure to various detergents. This affects not only the structure of lipid membrane but also its functionality, as rafts are physiologically involved in signal transduction, intracellular trafficking and cell migration [12]. These changes may decrease the efficiency of chemotherapeutic agents. Moreover, increased FA synthesis may also promote acylation of proteins and - among others - change their intracellular destination by targeting to rafts [10]. Another observation that may explain the role of FAS in tumor chemoresistance comes from studies on breast cancer cell lines. It has been reported that FAS overexpression coupled with hyperglycaemic growth conditions induces resistance to standard chemotherapeutics (5-fluorouracil, doxorubicin and paclitaxel) in MCF-7 and T47D cell lines. This may be explained by the impact of intensive endogenous synthesis of palmitate on cell homeostasis. In normal conditions, palmitate is a precursor for synthesis of ceramide, which is involved in intracellular signaling and mediates the apoptotic effects of ionizing radiation, chemotherapeutics or ischemia/reperfusion process. Increased FAS activity leads to intense synthesis of palmitate and then ceramide. Accumulation of ceramide is suspected to increase resistance to chemotherapeutics, which in non-accustomed cells stimulate apoptosis [13].
Currently, there are no reliable markers for identifying increased lipogenicity in a tumor, however, one method has been designed and patented by Swinnen (US20130115618) [14]. It utilizes electrospray ionization mass spectrometry tandem mass spectrometry (ESI-MS/MS) to compare the composition of a cancer cell membrane with healthy tissue. The phospholipids are identified by the intensity of ionized species expressed as the % of total intensity of all measured phospholipids. A shift toward monounsaturated phospholipids indicates a more resistant and aggressive lipogenic cancer phenotype. In detail, an increase in monounsaturated and decrease in polyunsaturated phospholipid species has been found to correlate with increased FAS gene expression and indicates an increased tumor resistance to lipid peroxidation and apoptosis, oxidative stress and chemotherapeutics [15]. Both the tumor and reference samples can be obtained from tissues, cells as well as cell extracts. For non-invasive samples authors suggest: urine, serum, whole blood or plasma concentrate, a precipitation from blood/plasma/urine (e.g. exosomes). The flexibility of the method enables to create a personalized model of treatment depending on patient’s condition and the type of tumor. It provides an insight into molecular profile of cancer, which may complement the clinical staging. Authors suggest this invention may also help monitor the effects of cancer therapy.
Fatty acid elongases (EVOVLs) participate in lipid metabolism. These endoplasmatic enzymes catalyze a four-step reaction of extending FAs into very long chain FAs [16]. So far, 7 different EVOVLs have been identified; ELOVL1, ELOVL3, and ELOVL6 act on saturated and monounsaturated FAs, whereas ELOVL 2, ELOVL 4, and ELOVL5 elongate PUFAs. Some of these enzymes have been studied in relation to breast (ELOVL2 and 5) and prostate (ELOVL7) cancer. Analysis of EVOVLs profile may be therefore utilized in diagnostics and profiling of various cancers (WO2013144325) [17]. In detail, the patent discloses the methods for measuring, in a biological sample, the expression of genes involved in fatty acid synthesis and elongation and comparing their expression with a reference genes in the same sample or with expression of genes in a reference sample. The analyzed set includes genes for FAS, various elongases, fatty acid desaturases, acetyl-CoA carboxylase and malonyl-CoA decarboxylase, as well as for protein-tyrosine phosphatase-like proteins, estradiol 17-beta- dehydrogenase 12 and sterol regulatory element-binding proteins 1c. This method may help diagnose cancer in a particular sample and more importantly, can determine the lipid phenotype of the cancer.
3. PRIMARY PREVENTION
CRC develops over the years and gradually transforms from normal epithelium through adenomatous pre-cancerous lesions to a full-blown tumor. Due to its growth dynamics, it is a suitable candidate for primary prevention. In this field, FAs have been studied as potential supplements that may delay or prevent CRC development. The most promising candidates so far are n-3 PUFAs, which show great tolerability profile and exhibit anti-inflammatory effects [18, 19]. However, despite theoretical background from basic science and promising epidemiological studies, intervention trials yielded mixed results and metaanalyses have failed to definitely support or overthrow their usefulness in CRC therapy [20, 21].
However, there are naturally occurring substances that may enhance n-3 PUFAs anti-cancer properties. Curcumin, a polyphenol derived from Curcuma longa, could play such a role. It displays pleiotropic biological effects both in vitro and in vivo i.e. it exerts anti-inflammatory, hypoglycemic, antioxidant, wound-healing, antimicrobial and anti-cancerous activity [22, 23]. This variety of actions is explained by a wide range of its molecular targets described in vitro - curcumin acts on a range of transcription factors (e.g. NF-κB, AP-1, and STAT-3), PGE2 and other inflammatory mediators, enzymes, growth factors, protein kinases, and cell-cycle regulatory proteins [24]. The safety, tolerability and nontoxicity of curcumin have already been proven in human clinical trials; however, its pharmacological efficiency (demonstrated by decrease in the level of the oxidative DNA adduct 3-(2-deoxy-β-di-erythro-pentafuranosyl)-pyr(1,2-α)-purin-10(3H) one (M1G)) has only been confirmed in surgical CRA samples taken from patients.
Curcumin holds promise as a primary prevention drug in high risk groups (e.g. smokers) as it reduces the formation of aberrant crypt foci, the precursors of colorectal polyps. In patients with familial adenomatous polyposis (FAP) who are a high risk group for CRC, treatment with combination of curcumin (480mg) and quercetin (20mg) orally decreased the number and size of polyps, without any reported toxicity [22]. However, due to small numbers of patients enrolled in the trials and varying methodology, the so-far reported results are inconsistent. Large RCTs are needed to determine its beneficial effects.
Halder et al. [25] studied the suspected synergy of curcumin and two n-3 PUFA formulations in vitro - a standard marine oil and a “smartfish” formulation enhanced with naturally occurring anti-oxidants. The agents in various combinations were incubated with MP2 cells and the cytotoxic effect was assessed by measuring caspase-3 expression, a mediator of programmed cell death. The experiment showed that high dose of curcumin successfully induced apoptosis in co-administration with marine oil n3-PUFA, whereas by adding anti-oxidants to the mixture the effect was potentiated. The study also verified the interactions between curcumin, “smartfish” n-3 PUFAs and NK cells-induced cytotoxicity. While “smartfish” oil partially induced NK-related cytotoxicity, adding curcuminoids significantly enhanced the effect. Unfortunately, the same study simultaneously showed that curcuminoids inhibit IFN-y production (an important anti-tumor cytokine) by NK cells, which may put obstacles in the way of its clinical utilization [25]. It is necessary to verify whether this ambivalent interaction between curcumin and cancer cells translates to in vivo models and, in the long term, to clinical trials.
Nevertheless, a new medical food and dietary supplement have already been developed and claimed in patents, for example fish oil, curcumin and hydroxytyrosol, and the combination of those components (WO2016046347, WO2016046347, US20160106696) [26-28]. Its clinical value in preventing cancer remains to be assessed.
4. TREATMENT
PUFAs give rise to various active metabolites, which display a wide range of biological actions. Thus, key enzymes of PUFAs metabolism represent another target to modulate tumor biology. A prime example of this strategy is the use of low-dose aspirin, which demonstrated (both in observational studies and RCTs) a protective effect in CRC prevention [29]. At first, this effect was attributed to the suppression of COXs, including COX-2 isoenzyme, whose expression is increased in 50% of colorectal adenomas and 85% of adenocarcinomas [29]. COX-2-derived PGs were proved to boost cell proliferation rate, promote angiogenesis and metastasis and suppress apoptosis [30]. However, many reports suggest that the doses of aspirin used in general population or in most RCTs are not high enough to effectively suppress COX-2. On the other hand, low-dose aspirin is perfectly capable of inhibiting COX-1 in platelets, which has been showed to induce COX-2 expression [29]. It is therefore possible that permanent COX-1 inactivation in platelets protects cells in intestinal mucosa from overexpression of COX-2.
Moreover, platelets can interact directly with cancer cells [31]. When cocultured with HT29 cells, human thrombocytes stimulate CRC cells toward more malignant gene expression phenotype. In turn, such “primed” CRC cells injected in mice can increase PGE2 systemic synthesis and platelet synthesis of TXA2. Importantly, aspirin administration counteracted these changes, either when used to pretreat platelets before coculturing with CRC cells, or when administered to mice injected with already primed HT29 [31]. Finally, it is possible that the action of aspirin on CRC cells is independent of COX-inhibition and interaction with platelets. This is supported by the observation that aspirin regulates sirtuin-1 expression and can modulate phosphatidylinositol 3-kinase-related intracellular signaling pathways [29]. However, extensive studies are needed to determine which mechanism is the most important in aspirin action.
Despite these ambiguities, aspirin is now officially recommended for CRC chemoprevention even though its usage confers significant side effects mainly associated with an increased risk of bleeding.
To solve this, selective COX-2 inhibitors (coxibs) were developed to target PGE-2 synthesis and prevent tumor-associated angiogenesis and growth. The key representant of this class, celecoxib, indeed exhibits chemoprotective effects against cancer [32]. Surprisingly enough, most of celecoxib`s anti-proliferative effects were found to be COX-independent and unique in the coxib`s family [30]. Celecoxib induces G1-phase arrest by inhibiting phosphoinositide-dependent kinase 1 (PDK-1), protein kinase B (PKB) and other cell-cycle kinases, and promotes apoptosis by decreasing the concentration of anti-apoptotic proteins Bcl-2, Bcl-xl, mcl-1 and survivin. Extrinsic apoptotic pathway (FAS-FADD) also takes part in celecoxib`s action [32]. Collectively, celecoxib affects the expression of over 1400 genes involved in, among others, immune response, inflammatory reaction, cell signaling and adhesion, response to stress, transforming growth factor-b signaling and apoptosis [30]. Given the vast pleiotropic effects of the molecule designed to affect solely AA metabolism, it might be enlightening to study the interactions between PUFA and coxib molecules, which may yield a better insight into the variety of PUFA metabolites. The beneficial properties of celecoxib have been confirmed both in vitro and in vivo, and currently the agent is approved as adjuvant treatment in FAP.
Worth mentioning, the celecoxib has low bioavailability and to induce the desired effect it must be administered at high doses, what in turn significantly increases the risk for adverse effects and undermines it as a potential chemoprevention drug. However, very recently Coulter et al. have developed a new multiple minibead formulation of celecoxib (WO2015176780) [33], which allows to lower the dosage and promises fewer adverse effects. It has already been claimed for prevention or treatment of CRC. Authors declare minibeads may be coated with polymers that ensure targeted release of celecoxib in the colon. Additionally, recent studies indicate that celecoxib might be used to break CRC resistance to chemotherapeutics like imatinib or cetuxizumab [34, 35].
Other agents that target PUFA metabolism, such as 5-LOX inhibitors, are currently under evaluation in the management of CRC. 5-LOX is reported to be overexpressed in the early stages of CRC and associated with markers of transformation of adenomatous polyps to cancer [36]. Historically, LOX inhibitors were reported to cause apoptosis of human leukemia blast cells and lung cancer cells. More recently, a new 5-LOX inhibitor, Zileuton, registered for asthma therapy, was proved to disrupt signaling in prostate cancer and induce apoptosis in pancreatic cancer cells [37-39], as well as to decrease proliferation in CRC cell lines and reduce the size of xenografted metastases [36]. Currently, no LOX inhibitors have been approved for cancer therapy.
One of prospective drugs is 12-methyltetradecanoic acid isolated from Cucumaria frondosa which inhibits 5-LOX and 12-LOX, and suppresses cancer cell proliferation in vitro (WO2001076588) [40]. However, it might be worthwhile to go even a step further and combine COX and LOX inhibitors to create a novel class of anti-cancer agents. Recent studies revealed that COX-2 and 5-LOX expression is tightly connected and balanced, i.e. when one of the enzymes is downregulated (e.g. by treatment or viral silencing), the other gets upregulated [41]. Thus, targeting them both may prove very efficient against CRC. There is a positive correlation between COX-2 and 5-LOX expression in CRC samples during cancer proliferation, migration and invasion [41]. Consequently, different analogues of indomethacin (COX-2 specific non-steroid anti-inflammatory drug), rofecoxib and celecoxib have been studied in search of agents displaying properties of dual inhibition. In effect, a new group of agents - di-ter-butyl phenols - has emerged, which inhibit selectively both COX-2 and 5-LOX [42]. The key representatives of this class are darbufelone, lycofelone and KME4. They all demonstrated their efficacy in in vitro studies [42]. Importantly, darbufelone proved to be more efficient as proliferation inhibitor than celecoxib, zileuton or their combination against LoVo CRC cells [41]. In turn, lycofelone has been studied most extensively and is the first to have reached clinical trials. In vitro, it triggered apoptosis in HCA-7 (human CRC cells) in a time- and dose-dependent manner, whereas in vivo it inhibited tumorigenesis in APC Min/+ mice [42]. More compounds are now being tested in in vitro studies.
Another class of agents having potential in CRC treatment are endocannabinoids. This heterogenous group of lipid mediators acts on G protein-coupled cannabinoid (CB) receptors expressed on neurons and immune cells. Their key representatives are N-arachidonoylethanolamine, named anandamide (AEA), and 2-arachidonoylglycerol (2-AG), both derived from AA. Anandamide displays promising anti-neoplastic effects in vitro in human (breast cancer, prostate cancer, cervical carcinoma, lymphoblastic cells) and animal cell lines (rat glioma, mouse lymphoblastic cells). Furthermore, it suppresses proliferation and promotes cell death in CRC cell lines via COX-2-depedent manner [43]; however its pro-apoptotic properties are less potent when compared to the AEA metabolites, prostaglandin-ethanolamine (PG-EA), such as PGE2-EA or PGD2-EA. Therefore, a composition including J-series PGs (PGJ-EAs) has been registered for treatment of non-melanoma skin cancer and CRC (US9328060) [44]. This patent offers a chance to specifically target CRC cells in which PGE2 expression is usually elevated, and at the same time to protect healthy tissues.
Other known acylethanolamides include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). In contrast to AEA, OEA has only one double bond in its structure and does not bind CB receptors (CBR), but instead activates peroxisome proliferator-activated receptor α (PPAR-α) and consequently induces satiety, inhibits weight gain and stimulates lipolysis and FA oxidation. Surprisingly, OEA also induces cell cycle arrest and apoptosis in cancer cells; nonetheless, its mechanism of action has not been elucidated yet. Thus, a pharmaceutical composition including OEA in combination with other active ingredients (e.g. vitamin A, carotenoids, ω-3 PUFA, ω-6 PUFA and/or conjugated LA), has been claimed in a patent to inhibit cell proliferation in tumors and cancers, including CRC (US20130172407) [45].
Another way to affect CRC biology is to target the key enzymes of tumor lipid metabolism. As mentioned before, cancers exhibit intense lipid turnover which is driven, among others, by their high proliferation rate [46]. Thus, excessive amounts of FAs are needed to provide the fuel for the cells, building materials for new lipid membranes and signaling molecules. This demand can be satisfied either by taking up the FAs from the bloodstream or synthesizing them de novo. In effect, cancer cells may use lipoprotein lipase (LPS) to degrade circulating triglycerides and take up the FAs with CD36 channel or FAS to synthesize their own [47, 48]. Although de novo synthesis seems to be the main source of FAs for most cancers, Kuemmerle et al. demonstrated that lipolytic pathway is also active in many cancer types [47
