Regulators of G-Protein Signaling (RGS) in Sporadic and Colitis-Associated Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common neoplasms worldwide. Among the risk factors of CRC, inflammatory bowel disease (IBD) is one of the most important ones leading to the development of colitis-associated CRC (CAC). G-protein coupled receptors (GPCR) are transmembrane receptors that orchestrate a multitude of signaling cascades in response to external stimuli. Because of their functionality, they are promising targets in research on new strategies for CRC diagnostics and treatment. Recently, regulators of G-proteins (RGS) have been attracting attention in the field of oncology. Typically, they serve as negative regulators of GPCR responses to both physiological stimuli and medications. RGS activity can lead to both beneficial and harmful effects depending on the nature of the stimulus. However, the atypical RGS-AXIN uses its RGS domain to antagonize key signaling pathways in CRC development through the stabilization of the ß-catenin destruction complex. Since AXIN does not limit the efficiency of medications, it seems to be an even more promising pharmacological target in CRC treatment. In this review, we discuss the current state of knowledge on RGS significance in sporadic CRC and CAC with particular emphasis on the regulation of GPCR involved in IBD-related inflammation comprising opioid, cannabinoid and serotonin receptors.

Empagliflozin attenuates intestinal inflammation through suppression of nitric oxide synthesis and myeloperoxidase activity in in vitro and in vivo models of colitis.

Inflammatory bowel diseases (IBD) are characterized by chronic and relapsing inflammation affecting the gastrointestinal (GI) tract. The incidence and prevalence of IBD are relatively high and still increasing. Additionally, current therapeutic strategies for IBD are not optimal. These facts urge todays' medicine to find a novel way to treat IBD. Here, we focused on the group of anti-diabetic drugs called gliflozins, which inhibit sodium glucose co-transporter type 2 (SGLT-2). Numerous studies demonstrated that gliflozins exhibit pleiotropic effect, including anti-inflammatory properties. In this study, we tested the effect of three gliflozins; empagliflozin (EMPA), dapagliflozin (DAPA), and canagliflozin (CANA) in in vitro and in vivo models of intestinal inflammation. Our in vitro experiments revealed that EMPA and DAPA suppress the production of nitric oxide in LPS-treated murine RAW264.7 macrophages. In in vivo part of our study, we showed that EMPA alleviates acute DSS-induced colitis in mice. Treatment with EMPA reduced macro- and microscopic colonic damage, as well as partially prevented from decrease in tight junction gene expression. Moreover, EMPA attenuated biochemical inflammatory parameters including reduced activity of myeloperoxidase. We showed that SGLT-2 inhibitors act as anti-inflammatory agents independently from their hypoglycemic effects. Our observations suggest that gliflozins alleviate inflammation through their potent effects on innate immune cells.

Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options.

Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.

AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice.

INTRODUCTION: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. METHODS: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1ß, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. RESULTS: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1ß expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. CONCLUSIONS: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis.

BACKGROUND: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper µ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. METHODS: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days. RESULTS: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. CONCLUSIONS: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Free Fatty Acid Receptors as new potential therapeutic target in inflammatory bowel diseases.

Family of Free Fatty Acid Receptors (FFARs), specific G protein-coupled receptors comprises of four members: FFAR1-4, where each responds to different chain length of fatty acids (FAs). Over the years, FFARs have become attractive pharmacological targets in the treatment of type 2 diabetes, metabolic syndrome, cardiovascular diseases and asthma; recent studies also point to their role in inflammation. It is now well-established that activation of FFAR1 and FFAR4 by long and medium chain FAs may lead to reduction of inflammatory state; FFAR2 and FFAR3 are activated by short chain FAs, but only FFAR2 was shown to alleviate inflammation, mostly by neutrophil inhibition. All FFARs have thus been proposed as targets in inflammatory bowel diseases (IBD). Here we discuss current knowledge and future directions in FFAR research related to IBD.

Dietary Carbohydrates and Lipids in the Pathogenesis of Leaky Gut Syndrome: An Overview.

This review summarizes the recent knowledge on the effects of dietary carbohydrates and lipids on the pathophysiology of leaky gut syndrome (LGS). Alterations in intestinal barrier permeability may lead to serious gastrointestinal (GI) disorders. LGS is caused by intestinal hyperpermeability due to changes in the expression levels and functioning of tight junctions. The influence of dietary habits on intestinal physiology is clearly visible in incidence rates of intestinal diseases in industrial and developing countries. Diseases which are linked to intestinal hyperpermeability tend to localize to Westernized countries, where a diet rich in fats and refined carbohydrates predominates. Several studies suggest that fructose is one of the key carbohydrates involved in the regulation of the intestinal permeability and its overuse may cause harmful effects, such as tight junction protein dysfunction. On the other hand, short chain fatty acids (mainly butyrate) at appropriate concentrations may lead to the reduction of intestinal permeability, which is beneficial in LGS. However, long chain fatty acids, including n-3 and n-6 polyunsaturated fatty acids have unclear properties. Some of those behave as components untightening and tightening the intestinal membrane.

Anti-Inflammatory Effect of Homo- and Heterodimers of Natural Enkephalinase Inhibitors in Experimental Colitis in Mice.

BACKGROUND: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. METHOD: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. RESULTS: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. CONCLUSION: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation.

Focus on current and future management possibilities in inflammatory bowel disease-related chronic pain.

INTRODUCTION: Visceral pain is a symptom reported by over 70% of inflammatory bowel disease (IBD) sufferers. So far, a single, specific cause of this debilitating state has not been established. Chronic pain is one of the most important factors decreasing the quality of life in IBD course. Concurrently, management of pain is the most challenging issue encountered by clinicians in IBD treatment. AREAS COVERED: This review focuses on pathophysiology of inflammatory bowel disease-caused visceral pain and explores currently available approaches to its management. We also covered recent pharmacological developments in the field. CONCLUSIONS: Pain-related disability has major effects on quality of life and on functional and social outcomes in IBD patients. Currently, there is no one standardized method of managing chronic visceral pain in IBD. Therefore, future development, focusing primarily on alleviating the pain, but also on reducing inflammation, is essential.

RGS proteins as targets in the treatment of intestinal inflammation and visceral pain: New insights and future perspectives.

Regulators of G protein signaling (RGS) proteins provide timely termination of G protein-coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti-inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS proteins. We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide.

New Peptide Inhibitor of Dipeptidyl Peptidase IV, EMDB-1 Extends the Half-Life of GLP-2 and Attenuates Colitis in Mice after Topical Administration.

Protease inhibition has become a possible new approach in inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV), is responsible for the inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently, we showed that the novel peptide analog of endomorphin-2, Tyr-Pro-D-ClPhe-Phe-NH2 (EMDB-1) is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract. We used two models of experimental colitis (induced by TNBS and DSS). The anti-inflammatory effect of EMDB-1 was assessed by the determination of macroscopic score, ulcer score, colonic wall thickness, as well as myeloperoxidase activity. Additionally, we measured the expression of GLP-2, GLP2R, and DPP IV in the colon of control and colitic animals treated with the test compound. The expression of GLP-2 and GLP2R in the serum and colon of IBD patients and healthy control subjects has been assessed. We showed that EMDB-1 elevates the half-life of GLP-2 in vitro and attenuates acute, semichronic, and relapsing TNBS as well as DSS-induced colitis in mice after topical administration. The anti-inflammatory action of EMDB-1 is associated with changes in the level of colonic GLP-2 but not DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs, and its inhibitors based on natural substrates, such as EMDB-1, have the potential to become valuable anti-inflammatory therapeutic agents.

Neuropharmacological characterization of the oneirogenic Mexican plant Calea zacatechichi aqueous extract in mice.

This study evaluates the neuropharmacological effects of the aqueous extract of the Mexican plant Calea zacatechichi Schltdl., which is commonly used in folk medicine to treat cough, asthma, and gastrointestinal disorders. Moreover, it has been used for centuries in traditional rituals based on divination and is thought to possess hallucinogenic activity. To test the neuropharmacological effects of the aqueous extract of C. zacatechichi we used mouse models of convulsions, an elevated plus-maze test and measured locomotor activity. We also evaluated the effect of the extract on antidepressant-like behavior in forced swim test, as well as on muscular strength in a grip test. Moreover the antinociceptive action of the extract was evaluated in the hot-plate and writhing tests. The chemical composition of the extract was evaluated using LC-MS techniques. The aqueous extract of C. zacatechichi did not affect any of the parameters measured in seizure models. It had also no influence on anxiety, exploratory behavior and muscular strength in the applied doses. On the other hand, the extract exhibited antinociceptive effect in the mouse model of abdominal pain. Chemical characterization of the extract showed the presence of chlorogenic acid, acacetin, and germacranolides. Based on this report we suggest that aqueous extract of C. zacatechichi has insignificant neuropharmacological effects in vivo and reduces abdominal pain perception. Our results, together with previous studies showing beneficial effects of the extracts obtained from C. zacatechichi suggest that these preparations may be used to treat medical conditions.

[Genetic factors in pathogenesis, course and treatment of inflammatory bowel diseases]. / Czynniki genetyczne w patogenezie, przebiegu i leczeniu nieswoistych chorób zapalnych jelit.

Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal disorders with alternating relapses and remissions. Two main types within IBD can be distinguished: Crohn's disease and ulcerative colitis. Considering the epidemiological, immunological and genetic data, it was concluded that IBD possess multifactorial etiology, where genetic and environmental factors form the immunological background for the disease. In this review we discuss the most important genes and their protein products in IBD etiology and their impact on IBD pharmacotherapy.

Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse model of inflammatory bowel diseases.

The nociceptin receptors (NOPs) are expressed in the gastrointestinal (GI) tract on muscle cell membranes and neurons, as well as the immune cells that infiltrate the mucosa. The involvement of NOPs in the pathophysiology of GI inflammation has been suggested, but due to the lack of selective NOP agonists, it never fully elucidated. Our aim was to characterize the anti-inflammatory and antinociceptive effect of the NOP agonist, SCH 221510 [3-endo-8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo [3.2.1]octan-3-ol], as a potential therapeutic strategy in the treatment of inflammatory bowel diseases (IBD). The anti-inflammatory action of SCH 221510 was determined after intraperitoneal, oral, and intracolonic administration of SCH 221510 (0.1-3.0 mg/kg once or twice daily) in mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Antinociceptive action of SCH 221510 was evaluated in the mouse model of mustard oil (MO)-induced abdominal pain. Relative NOP mRNA expression was assessed in patients with IBD using real-time reverse transcriptase-polymerase chain reaction. We found that the expression of NOP mRNA was significantly decreased in patients with IBD. The administration (0.1 and 1.0 mg/kg i.p. twice daily and 3 mg/kg p.o. twice daily) of SCH 221510 attenuated TNBS colitis in mice. This effect was blocked by a selective NOP antagonist [J-113397 [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one]]. The intracolonic injections of SCH 221510 did not improve colitis in mice. The antinociceptive effect of SCH 221510 was observed after oral administration of SCH 221510 in MO-induced pain tests in mice with acute colitis. In conclusion, our results show a potent anti-inflammatory and antinociceptive effect upon selective activation of NOP receptors and suggest that the NOP agonist SCH 221510 is a promising drug candidate for future treatment of IBD.

Chinese herbal medicines in the treatment of IBD and colorectal cancer: a review.

OPINION STATEMENT: Inflammatory bowel diseases (IBD) are a group of chronic inflammatory gastrointestinal (GI) disorders, mainly represented by Crohn's disease and ulcerative colitis. Although the etiology of IBD is not fully understood, there is substantial evidence that immunologic, genetic, and environmental factors are the main contributors in IBD pathogenesis. Conventional therapies for IBD include anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics, and biologicals, such as anti-TNFα antibodies. However, because of low efficacy and high risk of side effects, there is a clear need for the development of novel and efficient pharmacologic strategies in IBD treatment. Among various complementary and alternative medicine (CAM) approaches, which are used for the treatment of gastrointestinal (GI) disorders, traditional Chinese medicine (TCM) is one of the most developed and diversified. TCM encompasses methods and therapies that emerged over centuries and is based mostly on ethnic wisdom and observations transmitted from generation to generation. In the recent years, the efficacy of TCM as treatment of IBD has been extensively characterized in preclinical and clinical studies, which resulted in a significant number of research reports. Moreover, the popularity of TCM among patients with IBD has rapidly increased not only in Asia, but also in the Western hemisphere.

Cholesterol Nanofiber Patches with Sustainable Oil Delivery Eliminate Inflammation in Atopic Skin.

Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.

Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration.

We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous µ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a ß-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS.

Characterization of the effects of opiorphin and sialorphin and their analogs substituted in position 1 with pyroglutamic acid on motility in the mouse ileum.

Opiorphin and sialorphin are two recently discovered endogenous enkephalin-degrading enzyme inhibitors. Our aim was to characterize their effect on the mouse ileum motility and to investigate the role of glutamine in position 1. Opiorphin, sialorphin, and their analogs substituted in position 1 with pyroglutamic acid (pGlu) were synthesized by the solid-phase method using Fmoc chemistry. The effect of peptides on gastrointestinal (GI) motility was characterized using in vitro assays and in mouse model of upper GI transit. Opiorphin and sialorphin, but not their analogs, significantly increased electrical field-stimulated contractions in the mouse ileum in a δ-opioid receptor-dependent manner. Opiorphin, sialorphin, and their analogs did not influence the effect of [Met(5)]enkephalin on smooth muscle contractility in the mouse ileum in vitro. [Met(5)]enkephalin and sialorphin, but not opiorphin injected intravenously (1 mg/kg), significantly inhibited the upper GI transit. The intraperitoneal administration of peptides (3 mg/kg) did not change the mouse upper GI transit. In conclusion, this is the first study investigating the effect of opiorphin and sialorphin on the mouse ileum motility and demonstrating that glutamine in position 1 is crucial for their pharmacological action. Our results may be important for further structure-activity relationship studies on opiorphin and sialorphin and future development of potent clinical therapeutics aiming at the enkephalinergic system.

Pharmacological approaches to treat intestinal pain.

INTRODUCTION: Pain is one of the most substantial factors responsible for lowering quality of life in patients with intestinal diseases. Its multifactorial pathogenesis makes intestinal pain difficult to manage with currently available medications, especially considering the risk of serious adverse effects and exacerbation of underlying disease. AREAS COVERED: The most commonly administered drugs in intestinal pain are medications forming the so-called analgesic ladder, which act directly on pain sensation: acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids in full range of activity strength. However, there are also many groups of supportive medications, which target intestinal pain indirectly and therefore, differs in applicability depending on underlying conditions and their pathophysiology, e.g. antispasmodics, antidepressants, probiotics, and biological anti-inflammatory drugs. In this review, we concentrated on possible analgesic options in patients suffering from irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD), and colorectal cancer (CRC). Moreover, we examined future perspectives in treating abdominal pain with medications targeting transient receptor potential channels, the endocannabinoid system and other promising options, including new formulations of already known drugs and new peripherally restricted opioids. EXPERT OPINION: There is constant need for improvement of intestinal analgesia and novel pharmacological approaches, from which interaction with TRP receptors is a particularly promising direction.

Management of pain in colorectal cancer patients.

In this review we focus on the pathophysiology of CRC-related pain and discuss currently applied pain management. Pain is a symptom reported by over 70 % of colorectal cancer (CRC) patients. It remains a feared and debilitating consequence of both cancer and cancer-related treatment. There are many options for pain management in CRC, consisting of intravenous, oral or topical medications. In order to address the full spectrum of pain, proper treatment should address the nociceptive, neuropathic and/or psychogenic pain component. Currently available methods do not bring pain relief to satisfying number of patients and, if used improperly, can cause a number of complications. Therefore, future treatments should focus primarily on alleviating pain, but also on reducing possible side effects. In this article we cover recent and promising pharmacological and non- pharmacological developments emerging in the field of CRC treatment.