Antonio Montero Alcaide

Bioactive compounds isolated from microalgae in chronic inflammation and cancer

The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity.

Protective effect of polyphenols in an inflammatory process associated with experimental pulmonary fibrosis in mice

Polyphenols have been described to have a wide range of biological activities, and many reports, published during recent years, have highlighted the beneficial effects of phenolic compounds, illustrating their promising role as therapeutic tools in several acute and chronic disorders. The purpose of study was to evaluate, in an already-assessed model of lung injury caused by bleomycin (BLM) administration, the role of resveratrol and quercetin, as well as to explore the potential beneficial properties of a mango leaf extract, rich in mangiferin, and a grape leaf extract, rich in dihydroquercetin (DHQ), on the same model. Mice were subjected to intra-tracheal administration of BLM, and polyphenols were administered by oral route immediately after BLM instillation and daily for 7 d. Treatment with resveratrol, mangiferin, quercetin and DHQ inhibited oedema formation and body weight loss, as well as ameliorated polymorphonuclear infiltration into the lung tissue and reduced the number of inflammatory cells in bronchoalveolar lavage fluid. Moreover, polyphenols suppressed inducible nitric oxide synthase expression, and prevented oxidative and nitroxidative lung injury, as shown by the reduced nitrotyrosine and poly (ADP-ribose) polymerase levels. The degree of apoptosis, as evaluated by Bid and Bcl-2 balance, was also suppressed after polyphenol treatment. Finally, these natural products down-regulated cyclo-oxygenase-2, extracellular signal-regulated kinase phosphorylated expression and reduced NF-κBp65 translocation. Our findings confirmed the anti-inflammatory effects of resveratrol and quercetin in BLM-induced lung damage, and highlight, for the first time, the protective properties of exogenous administration of mangiferin and DHQ on experimental pulmonary fibrosis.

Pharmacological Control of Autophagy: Therapeutic Perspectives in Inflammatory Bowel Disease and Colorectal Cancer

Autophagy, an intracellular process involved in removing and recycling cellular components, plays a major role in growth, development, and responses to stress and pathogens. Autophagy is compromised in many human diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Autophagy malfunction is associated to an alteration of both innate and adaptative immune responses, defects in bacterial clearance, and malfunction of goblet and Paneth cells; all these perturbations are related to IBD and CRC pathogenesis. Preclinical data show that both inhibition and induction of autophagy have significant potential to be translated into the clinic. Inhibitors of TORC1 (rapamycin and rapalogs) have proven to be effective in IBD and in many models for CRCs; however, their clinical use has produced only modest success. Second generations of mTOR inhibitors, which target its kinase domain, have been more effective. Optimal antitumor efficacy is achieved by combination of agents with different molecular targets, such as proteasome or histone deacetylase inhibitors combined with autophagy inhibitors (hydroxychloroquine) or activators (everolimus). Clinical trials in course are assaying the effect of these compounds in combination with standard treatments of CRC. This review summarizes current knowledge about the autophagic machinery and its regulation, then it explores the relevance and impact of the malfunction of autophagy on the pathogenesis of IBD and CRC, and, finally, it discusses the therapeutic potential of molecules that regulate autophagy and their use for the treatment of these two diseases.

Inhibition of Chronic Ulcerative Colitis-associated Adenocarcinoma Development in Mice by VSL#3

Background:Colorectal cancer is the most severe complication in inflammatory bowel disease. This study aimed to investigate the effects of the probiotic VSL#3 when administered as either preventive or concurrent treatment in the progression from chronic colitis to colon cancer. Methods:Mice were exposed to 5, 10, and 15 cycles of dextran sulfate sodium (DSS); each cycle consisted of 0.7% DSS for 1 week followed by distilled water for 10 days. VSL#3 was administered either from 2 weeks before the colitis induction or from the first day of the colitis until being killed. After each period, macroscopic and histological studies, as well as analysis of inflammatory and tumor biomarkers, were performed. Results:Prophylactic or concurrent VSL#3 administration attenuated the disease activity index score and colon inflammation after 5, 10, and 15 cycles of DSS, as well as reduced the histological alterations and the incidence of colonic dysplastic lesions at the 3 periods studied. None of the animals receiving VSL#3 as a concurrent treatment developed carcinoma, which is in contrast to 5% and 20% of the mice following preventive VSL#3 administration, developing carcinoma at the 10th and the 15th cycles of DSS, respectively. In addition, the probiotic reduced the proliferating cell nuclear antigen labeling index, tumor necrosis factor alpha, interleukin-1&bgr;, interleukin-6 production, cyclooxygenase-2 expression, and increased interleukin-10 levels in colon tissue at the 3 periods assayed. Conclusions:VSL#3 administration reduced chronic inflammation and prevented or delayed the development of dysplasia and carcinoma in a mouse model of chronic colitis-associated cancer.

Expression patterns of sirtuin 1-AMPK-autophagy pathway in chronic colitis and inflammation-associated colon neoplasia in IL-10-deficient mice.

BACKGROUND Interleukin-10-deficient (IL-10 (-/-)) mice spontaneously develop chronic colitis and adenocarcinoma through the dysplasia sequence. Autophagy malfunction is associated to inflammatory bowel disease (IBD) and colorectal cancer (CRC) pathogenesis. Autophagy is regulated by silent information regulator-1 (SIRT1), a NAD+-dependent histone deacetylase. Our aim was to investigate the expression changes of SIRT1-AMPK-autophagy pathway in the progression from chronic colitis to CRC. METHODS We studied C57BL/6-IL-10-deficient mice between 6 and 18weeks of age. Macroscopic and histological analysis, and characterization of inflammatory and tumor biomarkers were performed. RESULTS IL-10-deficient mice developed colitis from the age of 6weeks onward. The severity of inflammation and dysplasia, and the proliferative activity increased gradually with age. IL-10 (-/-) mice were characterized by improved levels of TNF-α and decreased expression of SIRT1. Moreover, our findings show an increase in p-AMPK expression and an activation of the autophagy in IL-10 (-/-) mice from all stages, evidenced by the accumulation of LC3-II protein, the increase in Beclin 1 expression and the reduction in Bcl-2 levels. CONCLUSIONS SIRT1-AMPK-autophagy pathway may be involved in the maintenance of chronic inflammation and dysplasia development in the IL-10-deficient mice model. Modulation of this pathway could be a novel strategy for IBD and CRC treatment.

Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.

Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer.

The Algal Meroterpene 11-Hydroxy-1′-O-Methylamentadione Ameloriates Dextran Sulfate Sodium-Induced Colitis in Mice

Inflammatory bowel disease (IBD) is a complex class of immune disorders. Unfortunately, a treatment for total remission has not yet been found, while the use of natural product-based therapies has emerged as a promising intervention. The present study was aimed to investigate the anti-inflammatory effects of the algal meroterpene 11-hydroxy-1′-O-methylamentadione (AMT-E) in a murine model of dextran sodium sulphate (DSS)-induced colitis. AMT-E was orally administered daily (1, 10, and 20 mg/kg animal) to DSS treated mice (3% w/v) for 7 days. AMT-E prevented body weight loss and colon shortening and effectively attenuated the extent of the colonic damage. Similarly, AMT-E increased mucus production and reduced myeloperoxidase activity (marker for anti-inflammatory activity). Moreover, the algal meroterpene decreased the tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-10 levels, and caused a significant reduction of the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Our results demonstrate the protective effects of AMT-E on experimental colitis, provide an insight of the underlying mechanisms of this compound, and suggest that this class of marine natural products might be an interesting candidate for further studies on the prevention/treatment of IBD.

Dual Effects of Resveratrol on Cell Death and Proliferation of Colon Cancer Cells

ABSTRACT Colorectal cancer remains a main cause of deaths worldwide, and novel agents are being searched to treat this disease. Polyphenols have emerged as promising therapeutic tools in cancer. Resveratrol (3,5,4′-trihydoxy-trans-stilbene) induces cell death in different tumor cell lines, and it also stimulates the proliferation of specific breast and prostate cancer cell lines. Here, we studied the impact of resveratrol over a 100-fold concentration range on cell death and proliferation of HT-29 colorectal adenocarcinoma cells. After 96 h of treatment, a biphasic pattern was observed. At lower concentrations (1 and 10 μmol/l), resveratrol increased the cell number, as did the polyphenol quercetin. At 50 or 100 μmol/l, resveratrol reduced the cell number and increased the percentage of apoptotic or necrotic cells, thus indicating cytotoxicity. On HCT116 colon cancer cells, however, no proliferative properties of resveratrol were observed. Resveratrol-induced cytotoxicity on HT-29 cells was associated with NADPH oxidase activation and increased levels of histone γH2AX, a marker of DNA damage, paralleled by enhanced sirtuin 6 levels, likely as a repair mechanism. Overall, resveratrol may be an effective tool in anti-tumor chemotherapy. However, since under some conditions it may favor tumor cell growth, appropriate local concentrations must be achieved to minimize unwanted effects of resveratrol.