Targeting of G-quadruplex DNA with 99mTc(I)/Re(I) Tricarbonyl Complexes Carrying Pyridostatin Derivatives.

The main goal of this work was to elucidate the potential relevance of (radio)metal chelates of 99mTc and Re targeting G-quadruplex structures for the design of new tools for cancer theranostics. 99mTc provides the complexes with the ability to perform single-photon-emission computed tomography imaging studies, while the Re complexes should act as anticancer agents upon interaction with specific G4 DNA or RNA structures present in tumor tissues. Towards this goal, we have developed isostructural 99mTc(I) and Re(I) tricarbonyl complexes anchored by a pyrazolyl-diamine (Pz) chelator carrying a pendant pyridostatin (PDS) fragment as the G4-binding motif. The interaction of the PDF-Pz-Re (8) complex with different G4-forming oligonucleotides was studied by circular dichroism, fluorescence spectroscopy and FRET-melting assays. The results showed that the Re complex retained the ability to bind and stabilize G4-structures from different DNA or RNA sequences, namely those present on the SRC proto-oncogene and telomeric RNA (TERRA sequence). PDF-Pz-Re (8) showed low to moderate cytotoxicity in PC3 and MCF-7 cancer cell lines, as typically observed for G4-binders. Biodistribution studies of the congener PDF-Pz-99mTc (12) in normal mice showed that the complex undergoes a fast blood clearance with a predominant hepatobiliary excretion, pointing also for a high in vitro stability.

Risk of Second Tumors in Retinoblastoma Survivors after Ionizing Radiation: A Review.

Retinoblastoma (RB) is the most common ocular neoplasm in children, whose development depends on two mutational events that occur in both alleles of the retinoblastoma susceptibility gene (RB1). Regarding the nature of these mutational events, RB can be classified as hereditary if the first event is a germline mutation and the second one is a somatic mutation in retina cells or nonhereditary if both mutational events occur in somatic cells. Although the rate of survival of RB is significantly elevated, the incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the main cause of death in these patients. Effectively, RB patients present a higher risk of SMN incidence compared to other oncology patients. Furthermore, evidence confirms that hereditary RB survivors are at a higher risk for SMNs than nonhereditary RB survivors. Over the decades, some studies have been performed to better understand this subject, evaluating the risk of the development of SMNs in RB patients. Furthermore, this risk seems to increase with the use of ionizing radiation in some therapeutic approaches commonly used in the treatment of RB. This review aims to clarify the effect of ionizing radiation in RB patients and to understand the association between the risk of SMN incidence in patients that underwent radiation therapy, especially in hereditary RB individuals.

Acrocomia aculeata associated with doxorubicin: cardioprotection and anticancer activity.

Doxorubicin (Dox) is a chemotherapeutic agent widely used in the clinic, whose side effects include cardiotoxicity, associated with decreased antioxidant defenses and increased oxidative stress. The association of Dox with natural antioxidants can extend its use if not interfering with its pharmacological potential. In this study, we aimed to understand the effects and mechanisms of the aqueous extract of Acrocomia aculeata leaves (EA-Aa) in cancer cells and the co-treatment with Dox, in in vitro and in vivo models. It was found that EA-Aa showed a relevant decrease in the viability of cancer cells (K562 and MCF-7) and increased apoptosis and death. The Dox cytotoxic effect in co-treatment with EA-Aa was increased in cancer cells. The therapeutic association also promoted a change in cell death, leading to a higher rate of apoptosis compared to the Dox group, which induced necrosis. In addition, in non-cancer cells, EA-Aa enhanced red blood cell (RBC) redox state with lower hemolysis and malondialdehyde (MDA) content and had no in vitro nor in vivo toxicity. Furthermore, EA-Aa showed antioxidant protection against Dox-induced cytotoxicity in H9c2 cells (cardiomyoblast), partially mediated by the NRF2 pathway. In vivo, EA-Aa treatment showed a relevant decrease in MDA levels in the heart, kidney, and brain, evaluated in C57Bl/6 mice induced to cardiotoxicity by Dox. Together, our results proved the effectiveness of EA-Aa in potentiating Dox anticancer effects, with antioxidant and cardioprotective activity, suggesting EA-Aa as a potential Dox pharmacological adjuvant.

The Role of Apical Periodontitis Disease in the Development of Bisphosphonate-Related Osteonecrosis of the Jaw: An Animal Study.

BACKGROUND: Microorganisms and their by-products are responsible for establishing pulpal and periapical diseases. Healing is compromised in patients under bisphosphonate therapy, and the presence of periapical infections can potentially lead to the development of medication-related osteonecrosis of the jaw (MRONJ). This work aimed to evaluate if bisphosphonate therapy is a risk factor for MRONJ development in the presence of periapical lesions. METHODS: Two groups of 10 female Wistar rats were used. The experimental group received zoledronate (0.1 mg/kg) intraperitoneally, and the control received a saline solution, three times a week for three weeks. One week after the last injection, apical periodontitis was induced through pulpal exposure in the mandibular first molars. Twenty-one days later, the animals were intravenously injected with 99mTc-HMDP, and the radioactivity uptake by mandibular specimens was counted. In addition, sample radiographs and a histological examination were performed. RESULTS: The bone loss was higher in the control group when compared to the experimental group (p = 0.027). 99mTc-HMDP uptake in the control was reduced compared with the experimental group, although without statistical significance. CONCLUSIONS: In the presence of zoledronate therapy, apical periodontitis does not increase the risk of MRONJ development, and periapical lesions have lower bone resorption when compared to the control group.

Guidelines to Analyze Preclinical Studies Using Perinatal Derivatives.

The last 18 years have brought an increasing interest in the therapeutic use of perinatal derivatives (PnD). Preclinical studies used to assess the potential of PnD therapy include a broad range of study designs. The COST SPRINT Action (CA17116) aims to provide systematic and comprehensive reviews of preclinical studies for the understanding of the therapeutic potential and mechanisms of PnD in diseases and injuries that benefit from PnD therapy. Here we describe the publication search and data mining, extraction, and synthesis strategies employed to collect and prepare the published data selected for meta-analyses and reviews of the efficacy of PnD therapies for different diseases and injuries. A coordinated effort was made to prepare the data suitable to make statements for the treatment efficacy of the different types of PnD, routes, time points, and frequencies of administration, and the dosage based on clinically relevant effects resulting in clear increase, recovery or amelioration of the specific tissue or organ function. According to recently proposed guidelines, the harmonization of the nomenclature of PnD types will allow for the assessment of the most efficient treatments in various disease models. Experts within the COST SPRINT Action (CA17116), together with external collaborators, are doing the meta-analyses and reviews using the data prepared with the strategies presented here in the relevant disease or research fields. Our final aim is to provide standards to assess the safety and clinical benefit of PnD and to minimize redundancy in the use of animal models following the 3R principles for animal experimentation.

Anti-Algics in the Therapeutic Response of Breast and Urological Cancers.

The effect of anti-algics on tumor progression and the overall survival of patients is controversial and remains unclear. Herein, we disclose the in vitro effects of the local anesthetics lidocaine, ropivacaine, and levobupivacaine on breast (MCF7), prostate (PC3, LNCaP), and bladder (TCCSUP, HT1376) cancer cell lines, both as monotherapy and in combination with standard-of-care therapeutics. Assays for cell proliferation, viability, death profile, and migration were performed. Additionally, we explored the clinical outcomes of opioid use through a cross-sectional study involving 200 metastatic prostate cancer patients. The main clinical data collected included the type of opioid therapy administered, dosage, treatment duration, disease progression, and overall survival. Results obtained demonstrate that treatment with local anesthetics has a promising selective anti-tumor effect on these types of cancer, with higher effects when associated with docetaxel. This points out the use of local anesthetics as an added value in the treatment of prostate carcinoma patients. Alternatively, chronic opioid use was correlated with reduced overall survival (p < 0.05) and progression-free survival (p < 0.05) at each treatment line in the observational study. While these results provide valuable insights, larger prospective studies are imperative to comprehensively evaluate the clinical impact of opioid analgesics in prostate cancer patients.

Magnetic-Based Human Tissue 3D Cell Culture: A Systematic Review.

Cell-based assays, conducted on monolayer (2D) cultured cells, are an unquestionably valuable tool for biomedical research. However, three-dimensional (3D) cell culture models have gained relevance over the last few years due to the advantages of better mimicking the microenvironment and tissue microarchitecture in vivo. Recent magnetic-based 3D (m3D) cell culture systems can be used for this purpose. These systems are based on exposing magnetized cells to magnetic fields by levitation, bioprinting, or ring formation to promote cell aggregation into 3D structures. However, the successful development of these structures is dependent on several methodological characteristics and can be applied to mimic different human tissues. Thus, a systematic review was performed using Medline (via Pubmed), Scopus, and Web of Science (until February 2022) databases to aggregate studies using m3D culture in which human tissues were mimicked. The search generated 3784 records, of which 25 met the inclusion criteria. The usability of these m3D systems for the development of homotypic or heterotypic spheroids with or without scaffolds was explored in these studies. We also explore methodological differences specifically related to the magnetic method. Generally, the development of m3D cultures has been increasing, with bioprinting and levitation systems being the most used to generate homotypic or heterotypic cultures, mainly to mimic the physiology of human tissues, but also to perform therapeutic screening. This systematic review showed that there are areas of research where the application of this method remains barely explored, such as cancer research.

Methods and criteria for validating the multimodal functions of perinatal derivatives when used in oncological and antimicrobial applications.

Perinatal derivatives or PnDs refer to tissues, cells and secretomes from perinatal, or birth-associated tissues. In the past 2 decades PnDs have been highly investigated for their multimodal mechanisms of action that have been exploited in various disease settings, including in different cancers and infections. Indeed, there is growing evidence that PnDs possess anticancer and antimicrobial activities, but an urgent issue that needs to be addressed is the reproducible evaluation of efficacy, both in vitro and in vivo. Herein we present the most commonly used functional assays for the assessment of antitumor and antimicrobial properties of PnDs, and we discuss their advantages and disadvantages in assessing the functionality. This review is part of a quadrinomial series on functional assays for the validation of PnDs spanning biological functions such as immunomodulation, anticancer and antimicrobial, wound healing, and regeneration.

Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies.

The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches have benefitted from the application of human perinatal derivatives (PnD), biological mediators with proven benefits in several fields beyond oncology. To elucidate preclinical results and clinic outcomes achieved in the oncological field, we present a narrative review of the studies resorting to animal models to assess specific outcomes of PnD products. Recent preclinical evidence points to promising anticancer effects offered by PnD mediators isolated from the placenta, amniotic membrane, amniotic fluid, and umbilical cord. Described effects include tumorigenesis prevention, uncontrolled growth or regrowth inhibition, tumor homing ability, and adequate cell-based delivery capacity. Furthermore, PnD treatments have been described as supportive of chemotherapy and radiological therapies, particularly when resistance has been reported. However, opposite effects of PnD products have also been observed, offering support and trophic effect to malignant cells. Such paradoxical and dichotomous roles need to be intensively investigated. Current hypotheses identify as explanatory some critical factors, such as the type of the PnD biological products used or the manufacturing procedure to prepare the tissue/cellular treatment, the experimental design (including human-relevant animal models), and intrinsic pathophysiological characteristics. The effective and safe translation of PnD treatments to clinical practice relies on the collaborative efforts of all researchers working with human-relevant oncological preclinical models. However, it requires proper guidelines and consensus compiled by experts and health workers who accurately describe the methodology of tissue collection, PnD isolation, manufacturing, preservation, and delivery to the final user.

An Overview on Radiation Sensitivity in Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary breast and ovarian cancer (HBOC) syndrome is a condition in which individuals have an increased risk of developing different types of cancer when compared to the general population. BRCA1 repair associated (BRCA1) and BRCA2 repair associated (BRCA2) genes are tumor suppressor genes that play a crucial role in cell, by repairing DNA damage. Mutations in these genes are responsible for 25% of HBOC cases. Individuals with this syndrome are often subjected to diagnostic imaging techniques, as well as therapeutic options, that use ionizing radiation, so it is crucial to understand whether these individuals may present higher radiosensitivity and, therefore, its consequences. Several studies have been carried out to understand if the exposure to different ionizing radiation doses can induce cancer in individuals with HBOC. Some of these studies have shown that individuals with HBOC are hypersensitive to the ionizing radiation and, therefore, have neoplasms resulting from mutations in genes that are important in maintaining genomic stability. When mutated, genes no longer guarantee this stability and promote the induction of carcinogenesis. Oppositely, other studies show that there is no association between exposure to ionizing radiation and an increased risk of developing cancer. Thus, the results are inconsistent, and there is a great need to clarify this relationship. In this review, we present the characteristics of HBOC syndrome and the effects that ionizing radiation can induce in individuals who have it. In addition, we review the studies that have already been carried out on this subject.

The Potential Effect of Lidocaine, Ropivacaine, Levobupivacaine and Morphine on Breast Cancer Pre-Clinical Models: A Systematic Review.

Breast cancer (BC) is one of the most common types of cancer and the second leading cause of death in women. Local anaesthetics (LAs) and opioids have been shown to influence cancer progression and metastasis formation in several pre-clinical studies. However, their effects do not seem to promote consensus. A systematic review was conducted using the databases Medline (via PubMed), Scopus, and Web of Science (2010 to December 2021). Search terms included "lidocaine", "ropivacaine", "levobupivacaine", "morphine", "methadone", "breast cancer", "breast carcinoma" and "breast neoplasms" in diverse combinations. The search yielded a total of 784 abstracts for initial review, 23 of which met the inclusion criteria. Here we summarise recent studies on the effect of analgesics and LAs on BC cell lines and animal models and in combination with other treatment regimens. The results suggest that local anaesthetics have anti-tumorigenic properties, hence their clinical application holds therapeutic potential. Regarding morphine, the findings are conflicting, but this opioid appears to be a tumour-promoting agent. Methadone-related results are scarce. Additional research is clearly required to further study the mechanisms underlying the controversial effects of each analgesic or LA to establish the implications upon the outcome and prognosis of BC patients' treatment.

Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats.

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.

Study Protocol of a Multicenter Randomized Controlled Trial to Tackle Obesity through a Mediterranean Diet vs. a Traditional Low-Fat Diet in Adolescents: The MED4Youth Study.

Youth obesity is a strong predictor of adult obesity, which has well-known negative health consequences. Thus, addressing adult obesity requires tackling youth obesity. MED4Youth's main objective is to strengthen the link between the Mediterranean Diet (MD) and the health benefits against youth obesity and associated cardiovascular disease (CVD) risk factors, identifying positive effects exerted by an MD including sourdough bread and healthy products from the Mediterranean basis (chickpeas/hummus, nuts, and pomegranate juice). For this purpose, a multicenter randomized controlled trial in which an MD-based intervention will be compared to a traditional low-fat diet intervention will be carried out with 240 overweight and obese adolescents (13-17 years) from Spain, Portugal, and Italy. Both interventions will be combined with an educational web-application addressed to engage the adolescents through a learning-through-playing approach, using both educational materials and games. To assess the interventions, adherence to the MD, dietary records, physical activity, food frequency, sociodemographic, and quality of life questionnaires as well as classical anthropometric and biochemical parameters will be evaluated. Furthermore, an omics approach will be performed to elucidate whether the interventions can shape the gut microbiota and gut-derived metabolites to gain knowledge on the mechanisms through which the MD can exert its beneficial effects.

Oxidative stress in bladder cancer: an ally or an enemy?

Bladder cancer (BC) is the most common cancer of the urinary tract and despite all innovations, remains a major challenge due to high morbidity and mortality. Genomic and epigenetic analyses allowed the discovery of new genes and pathways involved in the pathogenesis and regulation of BC. However, the effect on mortality has been modest and the development of new targets for BC treatment are needed. Recent evidence suggests that cancer cells are under increased stress associated with oncogenic transformation, with changes in metabolic activity and increased generation of reactive oxygen species (ROS). The increased amounts of ROS in cancer cells are associated with stimulation of cellular proliferation, promotion of mutations and genetic instability, as well as alterations in cellular sensitivity to anticancer agents. Since these mechanisms occur in cancer cells, there is a close link between oxidative stress (OS) and BC with implications in prevention, carcinogenesis, prognosis, and treatment. We address the role of OS as an enemy towards BC development, as well as an ally to fight against BC. This review promises to expand our treatment options for BC with OS-based therapies and launches this approach as an opportunity to improve our ability to select patients most likely to respond to personalized therapy.

Acute myeloid leukemia sensitivity to metabolic inhibitors: glycolysis showed to be a better therapeutic target.

Cancer cells alter their metabolism by switching from glycolysis to oxidative phosphorylation (OXPHOS), regardless of oxygen availability. Metabolism may be a molecular target in acute myeloid leukemia (AML), where mutations in metabolic genes have been described. This study evaluated glycolysis and OXPHOS as therapeutic targets. The sensitivity to 2-deoxy-D-glucose (2-DG; glycolysis inhibitor) and oligomycin (OXPHOS inhibitor) was tested in six AML cell lines (HEL, HL-60, K-562, KG-1, NB-4, THP-1). These cells were characterized for IDH1/2 exon 4 mutations, reactive oxygen species, and mitochondrial membrane potential. Metabolic activity was assessed by resazurin assay, whereas cell death and cell cycle were assessed by flow cytometry. Glucose uptake and metabolism-related gene expression were analyzed by 18F-FDG and RT-PCR/qPCR, respectively. No IDH1/2 exon 4 mutations were detected. HEL cells had the highest 18F-FDG uptake and peroxides/superoxide anion levels, whereas THP-1 showed the lowest. 2-DG reduced metabolic activity in all cell lines with HEL, KG-1, and NB-4 being the most sensitive cells. Oligomycin decreased metabolic activity in a cell line-dependent manner, the THP-1 resistant and HL-60 being the most sensitive. Both inhibitors induced apoptosis and cell cycle arrest in a cell line- and compound-dependent manner. 2-DG decreased 18F-FDG uptake in HEL, HL-60, KG-1, and NB-4, while oligomycin increased the uptake in K-562. Metabolism gene expression had different responses to treatments. In conclusion, HEL and KG-1 show to be more glycolytic, whereas HL-60 was more OXPHOS dependent. Results suggest that AML cells reprogram their metabolism to overcome OXPHOS inhibition suggesting that glycolysis may be a better therapeutic target.

Tumour functional imaging by PET.

Carcinogenesis is a complex multistep process, characterized by changes at different levels, both genetic and epigenetic, which alter cell metabolism. Positron emission tomography (PET) is a very sensitive image modality that allows to evaluate oncometabolism. PET functionalities are immense, since by labelling a molecule that specifically intervenes in a biochemical regulatory pathway of interest with a positron-emitting radionuclide, we can easily image that pathway. Thus, PET makes possible imaging several metabolic processes and assessing risk prediction, screening, diagnosis, response to therapy, metastization and recurrence. In this paper, we provide an overview of different radiopharmaceuticals developed for PET use in oncology, with a focus on brain tumours, breast cancer, hepatocellular carcinoma, neuroendocrine tumours, bladder cancer and prostate cancer because for these cancer types PET has been shown to be valuable. Most of the described tracers are just used in the research environment, with the aim to assess if these tracers could be able to offer an improvement concerning staging/restaging, characterization and stratification of different types of cancer, as well as therapeutic response assessment. In pursuit of personalized therapy, we briefly discuss the more established metabolic tracers and describe recent work on the development of new radiopharmaceuticals, aware that there will continue to exist diagnostic challenges to face modern cancer medicine.

Iodine­131 metabolic radiotherapy leads to cell death and genomic alterations through NIS overexpression on cholangiocarcinoma.

Cholangiocarcinoma (CC) is an aggressive liver tumor with limited therapeutic options. Natrium­iodide symporter (NIS) mediates the uptake of iodine by the thyroid, representing a key component in metabolic radiotherapy using iodine­131 (131I) for the treatment of thyroid cancer. NIS expression is increased in CC, providing the opportunity for a novel therapeutic approach for this type of tumor. Thus, in this study, we aimed to evaluate therapeutic efficacy of 131I in two human CC cell lines. Uptake experiments analyzed the 131I uptake profiles of the tumor cell lines under study. The cells were irradiated with various doses of 131I to evaluate and characterize the effects of metabolic radiotherapy. NIS protein expression was assessed by immunofluorescence methods. Cell survival was evaluated by clonogenic assay and flow cytometry was used to assess cell viability, and the type of death and alterations in the cell cycle. The genomic and epigenetic characterization of both CC cells was performed before and after irradiation. NIS gene expression was evaluated in the CC cells by RT­qPCR. The results revealed that CC cells had a higher expression of NIS. 131I induced a decrease in cell survival in a dose­dependent manner. With the increasing irradiation dose, a decrease in cell viability was observed, with a consequent increase in cell death by initial apoptosis. Karyotype and array comparative genomic hybridization (aCGH) analyses revealed that both CC cell lines were near­triploid with several numerical and structural chromosomal rearrangements. NIS gene expression was increased in the TFK­1 and HuCCT1 cells in a time­dependent manner. On the whole, the findings of this study demonstrate that the presence of NIS in cholangiocarcinoma cell lines is crucial for the decreased cell viability and survival observed following the exposure of cholangiocarcinoma cells to 131I.

Evaluation of the efficacy of dentin hypersensitivity treatments-A systematic review and follow-up analysis.

OBJECTIVES: To compare the treatments used to treat dentin hypersensitivity (DH), based on its efficacy and effect duration. METHODS: Medline/PubMed, Cochrane Library, EMBASE and ClinicalTrials were searched for articles published between 1 January 2008 and 14 November 2018, in English, Portuguese or Spanish, reporting clinical trials, completed and with results. This systematic review protocol was registered in PROSPERO, number CRD42019121986. RESULTS: Seventy-four randomised clinical trials were included in the systematic review, reporting patients from 16 to 65 years old, with a clinical diagnosis of DH, that evaluate the efficacy of a desensitising product, compared to pre-treatment, used the evaporative method stimulation and the visual analogue scale. These studies evaluated 5366 patients and at least 9167 teeth. Seven follow-up periods were considered corresponding to an immediate, medium or long-time effect. Sixty-six studies were included in the quantitative synthesis. Glutaraldehyde with HEMA, glass ionomer cements and Laser present significant immediate (until 7 days) DH reduction. Medium-term (until 1 month) reduction was observed in stannous fluoride, glutaraldehyde with HEMA, hydroxyapatite, glass ionomer cements and Laser groups. Finally, long-term significant reduction was seen at potassium nitrate, arginine, glutaraldehyde with HEMA, hydroxyapatite, adhesive systems, glass ionomer cements and LASER. CONCLUSIONS: All active ingredients show efficacy in DH reduction in different follow-up times. Only in-office treatments are effective in immediate DH reduction, maintaining its efficacy over time. For long-time effects, at-home treatments can also be used. More standardised evaluation protocols should be implemented to increase the robustly of the results.

Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells.

A diet rich in fiber is associated with a low risk of developing colorectal cancer. Dietary fiber fermentation by intestinal microflora results in the production of butyrate, which has been reported as a chemopreventive agent and a histone deacetylase inhibitor (HDACi). Irinotecan is used as second-line treatment and induces adverse effects with serious life-threatening toxicities in at least 36% of patients. Our study intends to find a synergy that could improve the efficacy and decrease the toxicity of chemotherapy. Results demonstrate that milimolar concentrations of butyrate has an anti-proliferative effect in all three colon cancer cell lines under study, leading to a decrease on cell viability, expression of P21, P53 and ß-catenin, being able to modulate P-glycoprotein activity and to induce apoptosis by modulation of BAX/BCL-2 ratio. Combined therapy has a cytotoxic potential, resulting in a synergistic effect, and allows a reduction in irinotecan concentration needed to reduce IC50. This potential was verified in terms of cell viability and death, cell cycle and expression of P21 and P53. Butyrate and irinotecan act synergistically in the three cancer cell lines, despite the different genetic background and location, and inhibited tumor growth in a xenograft model. Butyrate is able to influence the mechanism of LS1034 cell line chemoresistance. Butyrate in combination with chemotherapeutic agents has an important role for the treatment of colorectal cancer. Such understanding can guide decisions about which patients with colorectal cancer may benefit from therapy with butyrate demonstrating the important role of diet in colorectal cancer treatment.

Ascorbic acid and colon cancer: an oxidative stimulus to cell death depending on cell profile.

Colorectal cancer is a major health problem worldwide with urgent need for new and effective anti-cancer approaches that allow treating, increasing survival and improving life quality of patients. At pharmacological concentrations, ascorbic acid (AA) exerts a selective cytotoxic effect, whose mechanism of cytotoxicity remains unsolved. It has been suggested that it depends on the production of extracellular hydrogen peroxide, using ascorbate radical as an intermediate. The aim of this study was to evaluate the effects induced by AA in three colon cancer cell lines, as well as, possible cell death mechanisms involved. Our results showed that pharmacological concentrations of AA induce anti-proliferative, cytotoxic and genotoxic effects on three colon cancer cell lines under study. We also found that AA can induce cell death by an increment of oxidative stress, but also mediating a ROS-independent mechanism, as observed in LS1034 cells. This work explores AA anti-tumoral effects and highlights its applicability in the treatment of CC, underlying the importance of proceeding to clinical trials.