// Nieves Gonzalez 1,* , Isabel Prieto 2,* , Laura del Puerto-Nevado 3,* , Sergio Portal-Nunez 4,* , Juan Antonio Ardura 4 , Marta Corton 5 , Beatriz Fernandez-Fernandez 6,7 , Oscar Aguilera 3 , Carmen Gomez-Guerrero 6 , Sebastian Mas 6 , Juan Antonio Moreno 6 , Marta Ruiz-Ortega 6 , Ana Belen Sanz 6,7 , Maria Dolores Sanchez-Nino 6,7 , Federico Rojo 8 , Fernando Vivanco 9 , Pedro Esbrit 4 , Carmen Ayuso 5 , Gloria Alvarez-Llamas 7,9 , Jesus Egido 1,6 , Jesus Garcia-Foncillas 3 , Alberto Ortiz 6,7 and Diabetes Cancer Connect Consortium 10 1 Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain 2 Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 3 Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 4 Bone and Mineral Metabolism laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 5 Genetics, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 6 Nephrology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 7 REDINREN, Madrid, Spain 8 Pathology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 9 Immunology, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain 10 Membership of the DiabetesCancerConnect Consortium is provided in the Acknowledgments * These authors have contributed equally to this work Correspondence to: Alberto Ortiz, email: // Keywords : hyperglycemia, inflammation, diabetic kidney disease, colon cancer, diabetes mellitus Received : September 07, 2016 Accepted : December 26, 2016 Published : January 03, 2017 Abstract Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2 ) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

/pdf/2017-update-on-the-relationship-between-diabetes-and-2o78rakfbl.pdf

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications.

Novel prospects of statins as therapeutic agents in cancer

Piceatannol (PIC) is known to have anticancer activity, which has been attributed to its ability to block the proliferation of cancer cells via suppression of the NF-kB signaling pathway. However, its effect on hypoxia-inducible factor (HIF) is not well known in cancer. In this study, PIC was loaded into bovine serum albumin (BSA) by desolvation method as PIC-BSA nanoparticles (NPs). These PIC-BSA nanoparticles were assessed for in vitro cytotoxicity, migration, invasion, and colony formation studies and levels of p65 and HIF-1α. Our results indicate that PIC-BSA NPs were more effective in downregulating the expression of nuclear p65 and HIF-1α in colon cancer cells as compared to free PIC. We also observed a significant reduction in inflammation induced by chemical colitis in mice by PIC-BSA NPs. Furthermore, a significant reduction in tumor size and number of colon tumors was also observed in the murine model of colitis-associated colorectal cancer, when treated with PIC-BSA NPs as compared to free PIC. The overall results indicate that PIC, when formulated as PIC-BSA NPs, enhances its therpautice potential. Our work could prompt further research in using natural anticancer agents as nanoparticels with possiable human clinical trails. This could lead to the development of a new line of safe and effective therapeutics for cancer patients.

/pdf/albumin-nano-encapsulation-of-piceatannol-enhances-its-3ot17ouw3n.pdf

Albumin Nano-Encapsulation of Piceatannol Enhances Its Anticancer Potential in Colon Cancer Via Downregulation of Nuclear p65 and HIF-1α.

Background: Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was to evaluate interleukin-1alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) in tissue specimens and saliva of patients with OSCC and OPMDs. Methods: Cytokines were evaluated in 60 tissue specimens of pathological lesions (OSCCs or OPMDs) and in 7 controls (normal oral mucosa, NOM) by immunohistochemistry and in saliva of 45 patients with OSCC or OPMDs and 9 controls (healthy volunteers) by enzyme-linked immunosorbent assays. Results: Immunohistochemical analysis revealed significantly higher expression of IL-8 in OSCC specimens and TNF-α in OSCCs and OPMDs with dysplasia as compared to NOM. Moreover, expression of TNF-α was significantly higher in oral leukoplakia and oral lichen planus without dysplasia, whereas expression of IL-8 only in oral leukoplakia without dysplasia in comparison with NOM. Salivary concentrations of all evaluated cytokines were significantly higher in patients with OSCC than in controls. Moreover, levels of IL-8 were significantly higher in saliva of patients with OPMDs with dysplasia as compared to controls and in OSCC patients as compared to patients with dysplastic lesions. There was also significant increase in salivary concentrations of IL-6, IL-8 and TNF-α in patients with OSCC as compared to patients with OPMDs without dysplasia. Conclusion: The study confirmed that proinflammatory, NF-kappaB dependent cytokines are involved in pathogenesis of OPMDs and OSCC. The most important biomarker of malignant transformation process within oral mucosa among all assessed cytokines seems to be IL-8. Further studies on a larger sample size are needed to corroborate these results.

https://www.mdpi.com/2077-0383/9/3/867/pdf

Evaluation of Proinflammatory, NF-kappaB Dependent Cytokines: IL-1α, IL-6, IL-8, and TNF-α in Tissue Specimens and Saliva of Patients with Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders.

Andrographis paniculata Nees is used as a functional food in Japan, Korea, India, and China. Andrographolide, a naturally occurring phytochemical identified in Andrographis paniculata, has been discovered to present anti-inflammatory and anticancer activities. Highly expressed interleukin (IL-8) has been detected in colorectal cancer and is implicated in angiogenesis. However, the effect and molecular mechanisms of IL-8 expression by andrographolide remain obscure in human colorectal cancer cells. The present study was aimed to investigate the effects of andrographolide on TNF-α-induced IL-8 expression and its underlying mechanisms. We found that andrographolide concentration-dependently inhibited TNF-α-induced IL-8 mRNA (2.23 ± 0.15 fold at 20 μM) and protein expression (4.78 ± 0.31 fold at 20 μM) and reduced the IL-8 transcriptional activity (2.59 ± 0.25 fold at 20 μM). TNF-α stimulated the membrane translocation of p47phox to activate reactive oxygen species (ROS)-producing NADPH oxidase (NOX). Furthermore, TNF-α induced Src and MAPKs (Erk1/2, p38 MAPK) phosphorylation, as well as NF-κB and AP-1 binding activities. We found that NF-κB and AP-1 were the critical transcription factors for TNF-α-induced IL-8 expression. Specific inhibitors and mutagenesis studies indicated that Src, Erk1/2, and p38 MAPK are related to TNF-α-induced IL-8. NOX-derived ROS and Src/MAPKs (Erk1/2 and p38 MAPK) functioned as upstream activators of NF-κB and AP-1, respectively. Taken together, andrographolide antagonizes TNF-α-induced IL-8 via inhibition of NADPH oxidase/ROS/NF-κB and Src/MAPKs/AP-1 signaling pathways in HCT116 colorectal cancer cells and then suppresses angiogenesis in the tumor microenvironment.

Andrographolide Antagonizes TNF-α-Induced IL-8 via Inhibition of NADPH Oxidase/ROS/NF-κB and Src/MAPKs/AP-1 Axis in Human Colorectal Cancer HCT116 Cells.

Recent investigations suggest that proinflammatory cytokines such as IL-6 and IL-8 are involved in the development of colorectal cancer (CRC), whereas statins, primarily used to decrease high levels of blood cholesterol, exhibit pleiotropic effects on carcinogenesis. In the present study we compared the expression of IL-8 and IL-6 in tissue samples of tumor and adjacent normal colon mucosa obtained from patients with advanced colorectal cancer (CRC). The analysis of mRNAs expression for these proinflammatory cytokines determined by RT-PCR showed a higher level of IL-8-mRNA in tumor tissue than in normal mucosa, while IL-6 was similarly expressed in tumor and normal tissue. The mean values of serum levels of both IL-6 and IL-8 were significantly higher in CRC patients than in healthy volunteers. Surgical removal of the tumor resulted in a prompt decrease of serum level of IL-8 already on the third day, whereas IL-6 level was transiently increased to become lower only after 7-10 days. Treatment of CRC with simvastatin (80 mg/day for 14 days) led to a significant decrease of serum IL-6, while the IL-8 level was less affected. The in vitro experiments on colorectal cancer-derived cell lines (HT-29 and Caco-2) demonstrated that application of simvastatin decreased generation of both IL-6 and IL-8. The differences in response of serum levels of IL-6 and IL-8 after tumor removal and treatment with simvastatin are novel observations suggesting distinct pathological roles of the two cytokines in CRC development. We conclude that 1) colorectal carcinogenesis is accompanied by increased synthesis and release of proinflammatory cytokines such as IL-6 and IL-8; 2) simvastatin therapy results in a decrease in serum level of proinflammatory cytokines, especially IL-6 in CRC and 3) simvastatin inhibits release of IL-8 and IL-6 from colorectal cell lines.

IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin

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IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin