Colorectal cancer I Endogenous opioid system I Opioid receptors I Opioids I Opium Abbreviations COX-2 cyclooxygenase-2. _ CRC colorectal cancer. _ DCs dendritic cells. _ DEN diethylnitrosamine. _ GPCR Gprotein-coupled receptors. _ IBD inflammatory bowel disease. _ IL-1β interleukin 1β. _ IL-6 interleukin 6. _ MMT methadone maintenance treatment. _ MOR mu opioid receptor. _ n-Cdh n-cadherin. _ NK natural killer cell. _ Nx propofol with epidural anesthesia. _ PGE2 prostaglandin E2. _ TJ tight junction. _ TLR toll-like receptor. _ TNFα tumor necrosis factor α. _ TPA 2-o-tetradecanoyl-phorbol-13-acetate. _ uPA urokinase plasminogen activator. _ ZO zonulaoccludens. Opinion statement So far, opioids have been successfully used to reduce cancer pain in patients in order to improve their quality of life. However, the use of opioids leads to numerous side effects such as constipation, drowsiness, nausea, itching, increased sweating and hormonal changes. In this review, we described the action of opioids in several molecular pathways significant for maintenance of the intestinal homeostasis including the impact on the intestinal epithelium integrity, changes in microbiome composition, modulation of the immune system or induction of apoptosis and inhibition of angiogenesis. We summed up the role of individual opioids in the processes involved in the growth and development of cancer and elucidated if targeting opioid receptors may constitute novel therapeutic option in colon cancer.

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In recent years, there has been a significant increase in the clinical use of organometallic compounds and metal complexes for therapeutic purposes including treatment of inflammatory bowel diseases (IBD). Their action is based on the inhibition of the inflow of pro-inflammatory cytokines, the elimination of free radicals or the modulation of intestinal microbiota. In addition, these compounds are intended for use in the diagnosis and treatment of colorectal cancer (CRC) which is often a consequence of IBD. The aim of this study is to critically discuss recent findings on the use of organometallic compounds and metal complexes in the treatment of IBD and CRC and suggest future trends in drug design.

Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signaling clearly indicate these receptors as the molecular targets of anti-cancer therapies. Despite the increasing number of tyrosine kinase inhibitors (TKIs) being investigated in clinical trials, acquired resistance to these drugs poses a serious therapeutic problem. In this study, we focused on a novel pan-FGFR inhibitor—CPL304110, currently being investigated in phase I clinical trials in adults with advanced solid malignancies. We analyzed the sensitivity of 17 cell lines derived from cancers with aberrant FGFR signaling, i.e. non-small cell lung cancer, gastric and bladder cancer to CPL304110. In order to explore the mechanism of acquired resistance to this FGFR inhibitor, we developed from sensitive cell lines their variants resistant to CPL304110. Herein, for the first time we revealed that the process of acquired resistance to the novel FGFR inhibitor was associated with increased expression of MET in lung, gastric, and bladder cancer cells. Overexpression of MET in NCI-H1703, SNU-16, RT-112 cells as well as treatment with HGF resulted in the impaired response to inhibition of FGFR activity. Moreover, we demonstrated that cells with acquired resistance to FGFR inhibitor as well as cells overexpressing MET displayed enhanced migratory abilities what was accompanied with increased levels of Pyk2 expression. Importantly, inhibition of both MET and Pyk2 activity restored sensitivity to FGFR inhibition in these cells. Our results demonstrate that the HGF/MET-Pyk2 signaling axis confers resistance to the novel FGFR inhibitor, and this mechanism is common for lung, gastric, and bladder cancer cells. Our study suggests that targeting of MET/Pyk2 could be an approach to overcome resistance to FGFR inhibition.

Purpose We hypothesize that different types of dietary fatty acids (FAs) affect gastrointestinal (GI) motility and visceromotor function and that this effect can be regulated by the fatty acid binding protein 4 (FABP4). Methods Mice were fed for 60 days with standard diet (STD), STD with 7% (by weight) coconut oil, rich in medium-chain FAs (MCFAs) (COCO), or with 7% evening primrose oil, rich in long-chain FAs (LCFAs) (EPO). In each group, half of the mice received FABP4 inhibitor, BMS309403 (1 mg/kg; i.p.) twice a week. Body weight (BW) and food intake were measured; well-established tests were performed to characterize the changes in GI motility and visceral pain. White adipose tissue and colonic samples were collected for cell culturing and molecular studies. Results COCO significantly increased GI transit, but not colonic motility. COCO and EPO delayed the onset of diarrhea, but none affected the effect of loperamide. EPO reduced BW and increased the visceromotor response (VMR) to colorectal distension (CRD). COCO and EPO reduced differentiation of preadipocytes. Treatment with BMS309403: (1) reversed the effects induced by COCO in physiological conditions and in mouse models of diarrhea; (2) prevented the effects of EPO on BW, VMR to CRD and castor oil-induced diarrhea; (3) affected proliferation of preadipocytes; (4) changed the expression of Fabp4 in colonic and adipocyte samples from COCO and EPO. Conclusion Modifying dietary intake of MCFAs and LCFAs may be used to control GI motility or visceral pain and thus modulate the symptoms of functional GI disorders. The effect is dependent on the expression of FABP4. Keywords Medium-chain fatty acids • Long-chain fatty acids • Coconut oil • Fatty acid binding protein 4 • Gastrointestinal motility • Irritable bowel syndrome Abbreviations CLA Conjugated LA COCO Coconut oil Ct * Jakub Fichna