Ataxia telangiectasia and Rad3-related (ATR) inhibition by VE-822 potently reversed 5-flourouracil resistance in colorectal cancer cells through targeting DNA damage response.

BACKGROUND: VE-822 is a novel inhibitor of ATR, a key kinase involved in the DNA damage response pathway. The role of ATR inhibition in reversing drug resistance in various cancer types has been investigated. Therefore, this study investigated the effects of ATR inhibition by VE-822 on reversing 5-fluorouracil (5-FU) resistance in colorectal cancer cell line (Caco-2). METHODS: Caco-2 and 5-FU resistance Caco-2 (Caco-2/5-FU) cells were treated with 5-FU and VE-822, alone and in combination. Cell proliferation and viability were assessed by MTT assay and Trypan Blue staining. P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) activities were measured by Rhodamine123 accumulation and uptake assay. The mRNA levels of P-gp, MRP-1, ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) were measured by qRT-PCR. Western blot was used to measure the protein levels of P-gp, MRP-1, γ-H2AX, ATR and CHK1 in cells. 8-Oxo-2'-deoxyguanosine (8-oxo-dG) levels were determined via ELISA. Apoptosis was evaluated by ELISA death assay, DAPI staining and lactate dehydrogenase (LDH) assay. RESULTS: The Caco-2/5-FU cells showed lower levels of 5-FU mediated proliferation inhibition in comparison to Caco-2 cells. VE-822 decreased the IC50 value of 5-FU on resistant cells. In addition, the expression levels and activity of P-gp and MRP-1 were significantly decreased in resistant cells treated with VE-822 (P < 0.05). The combination of 5-FU and VE-822 increased apoptosis in Caco-2/5-FU cells by downregulating CHK1 and ATR and upregulating γ-H2AX and 8-oxo-dG. CONCLUSION: The simultaneous treatment of resistant colorectal cancer cells with 5-FU and ATR inhibitor, VE-822, was demonstrated to be effective in reversing drug resistance and potentiating 5-FU mediated anticancer effects via targeting DNA damage.

Interactions of melatonin with various signaling pathways: implications for cancer therapy.

Melatonin is a neuro-hormone with conserved roles in evolution. Initially synthetized as an antioxidant molecule, it has gained prominence as a key molecule in the regulation of the circadian rhythm. Melatonin exerts its effect by binding to cytoplasmic and intra-nuclear receptors, and is able to regulate the expression of key mediators of different signaling pathways. This ability has led scholars to investigate the role of melatonin in reversing the process of carcinogenesis, a process in which many signaling pathways are involved, and regulating these pathways may be of clinical significance. In this review, the role of melatonin in regulating multiple signaling pathways with important roles in cancer progression is discussed, and evidence regarding the beneficence of targeting malignancies with this approach is presented.

Molecular mechanisms underlying ameliorative impact of melatonin against age-dependent chronic arsenic toxicity in rats' brains.

Accumulation of random molecular damage such as oxidative DNA damage and inflammation is extremely found to be involved in the aging process. Due to extreme energy requirements and high lipid levels, the brain is more susceptible to oxidative damage during aging especially under exposure to toxic elements such as arsenic. Therefore, this study was aimed to evaluate the ameliorative effects of melatonin, as a neurohormone, on the arsenic-induced behavioral abnormalities, and the underlying mechanisms. Forty-eight rats, as young and old aged groups were exposed to 5.55 g/kg body weight arsenic for 4 weeks and then 10 mg/kg melatonin for 2 weeks. Our results showed that arsenic led to anxiety-like behavioral abnormalities in rats. Increased oxidative stress-induced damage to DNA, lipids and proteins, decreased potential of antioxidant defense system, induced apoptosis, elevated inflammation, and alteration in the histology of cortical region of brains are observed in the rats exposed to arsenic. These effects were more prominent in aged rats in comparison to young rats. Melatonin successfully attenuates arsenic induced adverse effects on the brain in both age groups. In conclusion, our study shows that melatonin has significant ameliorative impact on age-dependent cytotoxicity of arsenic in rats' brains.

Nanotechnology-based advances in the efficient delivery of melatonin.

N-[2-(5-methoxy-1H-indol-3-yl) ethyl] or simply melatonin is a biogenic amine produced by pineal gland and recently recognized various other organs. Because of a broad range of biological function melatonin is considered as a therapeutic agent with high efficacy in the treatment of multiple disorders, such as cancer, degenerative disorders and immune disease. However, since melatonin can affect receptors on the cellular membrane, in the nucleus and can act as an anti-oxidant molecule, some unwanted effects may be observed after administration. Therefore, the entrapment of melatonin in biocompatible, biodegradable and safe nano-delivery systems can prevent its degradation in circulation; decrease its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. Because of this, nanoparticles have been used to deliver melatonin in multiple studies, and the present article aims to cumulatively illustrate their findings.

Parasympathetic, but not sympathetic denervation, suppressed colorectal cancer progression.

Disruption in the nerve-tumor interaction is now considered as a possible anticancer strategy for treating various cancer types, particularly colorectal cancer. However, the underlying mechanisms are not still fully understood. Therefore, the present study aimed to evaluate the effects of sympathetic and parasympathetic denervation on the inhibition of colorectal cancer progression in early and late phases and assess the involvement of nerve growth factor in denervation mediated anticancer effects. One-hundred and fifty male Wistar rats were assigned into 15 groups. Seven groups comprising the control group, 1,2-dimethylhydrazine (DMH) group, sympathetic denervation group (celiac-mesenteric ganglionectomy and guanethidine sulphate administration), parasympathetic denervation group (vagotomy and atropine administration), and combination group were used in the early-stage protocol. For the late-stage protocol, eight groups comprising the control, DMH, surgical and pharmacological sympathetic and parasympathetic denervation groups, combination group, and 5-flourouracil group were considered. After 8 weeks, sympathetic and parasympathetic denervation significantly reduced ACF numbers in rats receiving DMH. On the other hand, in the late stages, parasympathetic but not sympathetic denervation resulted in significant reductions in tumor incidence, tumor volume and weight, cell proliferation (indicated by reduced immunostaining of PCNA and ki-67), and angiogenesis (indicated by reduced immunostaining of CD31 and VEGF expression levels), and downregulated NGF, ß2 adrenergic, and M3 receptors. It can be concluded that parasympathetic denervation may be of high importance in colon carcinogenesis and suggested as a possible therapeutic modality in late stages of colorectal cancer.

Melatonin increases 5-flurouracil-mediated apoptosis of colorectal cancer cells through enhancing oxidative stress and downregulating survivin and XIAP.

Introduction: Colorectal cancer (CRC) is one of the most lethal human malignancies with a global alarming rate of incidence. The development of resistance against common chemotherapeutics such as 5-fluorouracil (5-FU) remains a big burden for CRC therapy. Therefore, we investigated the effects of melatonin on the increasing 5-FU- mediated apoptosis and its underlying mechanism in SW-480 CRC cell line. Methods: The effects of melatonin and 5- FU, alone or in combination, on cell proliferation were evaluated using an MTT assay. Further, Annexin-V Flow cytometry was used for determining the effects of melatonin and 5-FU on the apoptosis of SW-480 cell lines. The expression levels of Bax, Bcl-2, pro-caspase-3/activated caspase 3, X-linked inhibitor of apoptosis proteins (XIAP), and survivin were measured after 48 hours incubation with drugs. Cellular levels of reactive oxygen species (ROS), catalase, superoxide dismutase and glutathione peroxidase were also evaluated. Results: Melatonin and 5-FU significantly decreased the cell proliferation of SW-480 cells. Combination of 5-FU with melatonin significantly decreased the IC50 value of 5-FU from 100 µM to 50 µM. Moreover, combination therapy increased intracellular levels of ROS and suppressed antioxidant enzymatic activities (P < 0.05). Treatment with either melatonin or 5-FU resulted in the induction of apoptosis in comparison to control (P > 0.05). XIAP and survivin expression levels potently decreased after combination treatment with melatonin and 5-FU (P < 0.05). Conclusion: We demonstrated that melatonin exerts a reversing effect on the resistance to apoptosis by targeting oxidative stress, XIAP and survivin in CRC cells. Therefore, more studies need for better understanding of underlying mechanisms for beneficial effects of combination of melatonin and 5-FU.

Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer.

Phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important proliferative signaling pathways with critical undeniable function in various aspects of cancer initiation/progression, including proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. On the other hand, numerous genetic alterations in the key genes involved in the PI3K/AKT/mTOR signaling pathway have been identified in multiple solid and hematological tumors. In addition, accumulating recent evidences have demonstrated a reciprocal interaction between this signaling pathway and microRNAs, a large group of small non-coding RNAs. Therefore, in this review, it was attempted to discuss about the interaction between key components of PI3K/AKT/mTOR signaling pathway with various miRNAs and their importance in cancer biology.

SIRT1: a promising therapeutic target in type 2 diabetes mellitus.

A significant increase in the worldwide incidence and prevalence of type 2 diabetic mellitus (T2DM) has elevated the need for studies on novel and effective therapeutic strategies. Sirtuin 1 (SIRT1) is an NAD + dependent protein deacetylase with a critical function in the regulation of glucose/lipid metabolism, insulin resistance, inflammation, oxidative stress, and mitochondrial function. SIRT1 is also involved in the regulation of insulin secretion from pancreatic ß-cells and protecting these cells from inflammation and oxidative stress-mediated tissue damages. In this regard, major SIRT1 activators have been demonstrated to exert a beneficial impact in reversing T2DM-related complications including cardiomyopathy, nephropathy, retinopathy, and neuropathy, hence treating T2DM. Therefore, an accumulating number of recent studies have investigated the efficacy of targeting SIRT1 as a therapeutic strategy in T2DM. In this review we aimed to discuss the current understanding of the physiological and biological roles of SIRT1, then its implication in the pathogenesis of T2DM, and the therapeutic potential of SIRT1 in combating T2DM.

Doxorubicin loaded magnetism nanoparticles based on cyclodextrin dendritic-graphene oxide inhibited MCF-7 cell proliferation.

Doxorubicin (DOX) is an effective chemotherapeutic agent used for the treatment of various types of cancer. However, its poor solubility, undesirable side effects, and short half-life have remained a challenge. We used a formulation based on graphene oxide as an anticancer drug delivery system for DOX in MCF-7 breast cancer cells, to address these issues. In vitro release studies confirmed that the synthesized formulation has an improved release profile in acidic conditions (similar to the tumor microenvironment). Further in vitro studies, including MTT, uptake, and apoptosis assays were performed. The toxic effects of the nanocarrier on the kidney, heart and liver of healthy rats were also evaluated. We observed that the DOX-loaded carrier improved the cytotoxic effect of DOX on the breast cell line compared to free DOX. In summary, our results introduce the DOX-loaded carrier as a potential platform for in vitro targeting of cancer cells and suggest further studies are necessary to investigate its in vivo anti-cancer potential.

In vitro and in vivo anticancer effects of syringic acid on colorectal cancer: Possible mechanistic view.

This study aimed to evaluate the in vitro effects of syringic acid on human colorectal cancer cells (SW-480) and the effect of orally administered syringic acid on in vivo models of colorectal cancer induced in rats by administration of 1,2-dimethylhydrazine (DMH). In vitro effects of syringic acid treatment on human colorectal cancer SW-480 cell lines were assessed by performing cell proliferation assay (MTT and Trypan Blue staining), apoptosis assays (TUNEL assay, Annexin-V/PI flowcytometry and lactate dehydrogenase release assay), measuring reactive oxygen species (ROS), antioxidant enzymes and DNA damage, and evaluating protein levels of proliferative genes, and autophagy markers. In vitro anti-cancer roles of syringic acid were studied in rats with DMH-induced colorectal cancer cells. The effect of orally administered syringic acid (50 mg/kg) on tumor growth and incidence was studied in four groups (n = 6) of animals injected with DMH and treated for 15 weeks. Syringic acid treatment resulted in a significant dose-dependent inhibition of cellular proliferation, induction of apoptosis through increasing cellular ROS and DNA damage levels, as well as downregulating major proliferative genes. In vivo, treatment of rats with syringic acid demonstrated a statistically significant tumor volume and incidence reduction when compared to the control. This is the first study demonstrating an in vivo growth inhibitory effect of orally administered syringic acid on colorectal tumors in rats.

DNA damage response and breast cancer development: Possible therapeutic applications of ATR, ATM, PARP, BRCA1 inhibition.

Breast cancer is the most common and significant cancers in females regarding the loss of life quality. Similar to other cancers, one of the etiologic factors in breast cancer is DNA damage. A plethora of molecules are responsible for sensing DNA damage and mediating actions which lead to DNA repair, senescence, cell cycle arrest and if damage is unbearable to apoptosis. In each of these, aberrations leading to unrepaired damage was resulted in uncontrolled proliferation and cancer. Another cellular function is autophagy defined as a process eliminating of unnecessary proteins in stress cases involved in pathogenesis of cancer. Knowing their role in cancer, scholars have tried to develop strategies in order to target DDR and autophagy. Further, the interactions of DDR and autophagy plus their regulatory role on each other have been focused simultaneously. The present review study has aimed to illustrate the importance of DDR and autophagy in breast cancer according to the related studies and uncover the relation between DDR and autophagy and its significance in breast cancer therapy.

Combination of quercetin and exercise training attenuates depression in rats with 1,2-dimethylhydrazine-induced colorectal cancer: Possible involvement of inflammation and BDNF signalling.

NEW FINDINGS: What is the central question of this study? What are the alleviative effects of the combination of exercise training and quercetin supplementation on colorectal cancer-related depression in rats with 1,2-dimethylhydrazine-induced colorectal cancer and what is the corresponding signalling pathway? What is the main finding and its importance? We showed that the combination of exercise training and quercetin supplementation resulted in a significant decrease in tumour incidence and improvement in depressive-like behaviours through modulation of the BDNF/TrKß/ß-catenin axis in the prefrontal cortex. ABSTRACT: In addition to physical problems, depression is considered to be one of the most important challenges for patients with various types of cancers, particularly colorectal cancer. Inflammation and upregulation of brain neurotrophic factors are two major links between cancer and depression. In this study, we aimed to evaluate the alleviative effects of quercetin and exercise training on depressive-like behaviours in rats with 1,2-dimethylhydrazine (DMH)-induced colorectal cancer and to investigate the underlying mechanisms. Animals were assigned into the following five groups: (i) control group; (ii) DMH (20 mg kg-1 s.c., once a week for 10 weeks); (iii) DMH for 10 weeks, followed by quercetin (50 mg kg-1 p.o., once per week) for 12 weeks; (iv) DMH for 10 weeks, followed by exercise training for 12 weeks; and (v) DMH for 10 weeks, followed by quercetin and exercise training for 12 weeks. The DMH-treated rats showed an increase in depressive-like behaviours in both open field and forced swimming tests. Histopathological examination revealed neural damage and reduced Nissl bodies in the prefrontal cortex. In addition, administration of DMH increased inflammatory cytokines in the serum, prefrontal cortex and tumour tissues and decreased the expression levels of brain-derived neurotrophic factor (BDNF), tyrosine kinase ß receptor (TrKß) and ß-catenin in the cortex. In contrast, treatment with quercetin and exercise training effectively alleviated all the above-mentioned DMH-associated behavioural, biochemical and histopathological alterations without changing its anti-tumour activity. Taken together, our results show that the combination of quercetin and exercise training exerts potent anti-tumour and anti-depressive effects through suppression of inflammation and upregulation of the BDNF/TrKß/ß-catenin axis in the prefrontal cortex.

Melatonin: An atypical hormone with major functions in the regulation of angiogenesis.

Melatonin (N-acetyl-5-methoxytryptamine), a pleotropic molecule with a wide distribution, has received considerable attention in recent years, mostly because of its various major effects on tissues or cells since it has both receptor-dependent and receptor-independent actions over a wide range of concentrations. These biological and physiological functions of melatonin include regulation of circadian rhythms by modulating the expression of core oscillator genes, scavenging the reactive oxygen species and reactive nitrogen species, modulating the immune system and inflammatory response, and exerting cytoprotective and antiapoptotic effects. Given the multiple critical roles of melatonin, dysregulation of its production or any disruption in signaling through its receptors may have contributed in the development of a wide range of disorders including type 2 diabetes, aging, immune-mediated diseases, hypertension, and cancer. Herein, we focus on the modulatory effects of melatonin on angiogenesis and its implications as a therapeutic strategy in cancer and related diseases.

Quercetin attenuated oxidative DNA damage through NRF2 signaling pathway in rats with DMH induced colon carcinogenesis.

Accumulating recent studies have demonstrated the preventive and therapeutic effects of polyphonic compounds such as quercetin in colorectal cancer. Therefore, we aimed to evaluate the underlying mechanisms for positive effects of quercetin in rats with 1,2-dimethylhydrazine (DMH)- induced colorectal cancer. For this purpose, male Wistar rats were classified as 6 groups, including group 1 without any intervention, group 2 as quercetin received rats (50 mg/kg), groups 3 as DMH received rats (20 mg/kg) group 4-6 DMH and quercetin received rats. DNA damage, DNA repair, the expression levels and activities of enzymic antioxidants, non-enzymic antioxidants, and NRF2/Keap1 signaling were evaluated in colon tissues of all groups. Our results showed significant suppression of DNA damage and induction of DNA repair in DMH + Quercetin groups, particularly in entire-period in comparison to other groups (p < .05). The expression levels and activities of enzymic and non-enzymic antioxidants were increased in DMH + Quercetin groups (p < .05). Lipid and protein peroxidation were significantly suppressed in DMH + Quercetin groups (p < .05). In addition, quercetin also modulated NRF2/Keap1 signaling and its targets, detoxifying enzymes in DMH + Quercetin groups. Our finding demonstrated that quercetin supplementation effectively reversed DMH-mediated oxidative stress and DNA damage through targeting NRF2/Keap1 signaling pathway.

Targeting PI3K/Akt/mTOR signaling pathway by polyphenols: Implication for cancer therapy.

Cancer is one of the biggest challenges facing medicine and its cure is regarded to be the Holy Grail of medicine. Therapy in cancer is consisted as various artificial cytotoxic agents and radiotherapy, and recently immunotherapy. Recently much attention has been directed to the use of natural occurring agents in cancer therapy. One of the main group of agents utilized in this regard is polyphenols which are found abundantly in berries, fruits and vegetables. Polyphenols show to exert direct and indirect effects in progression of cancer, angiogenesis, proliferation and enhancing resistance to treatment. One of the cellular pathways commonly affected by polyphenols is PI3K/Akt/mTOR pathway, which has far ranging effects on multiple key aspects of cellular growth, metabolism and death. In this review article, evidence regarding the biology of polyphenols in cancer via PI3K/Akt/mTOR pathway is discussed and their application on cancer pathophysiology in various types of human malignancies is shown.

Critical roles of long noncoding RNAs in breast cancer.

Breast cancer is a major clinical challenge that affects a wide range of the female population and heavily burdens the health system. In the past few decades, attempts have been made to understand the etiology of breast cancer, possible environmental risk factors, and the genetic predispositions, pathogenesis, and molecular aberrations involved in the process. Studies have shown that breast cancer is a heterogeneous entity; each subtype has its specific set of aberrations in different cell signaling pathways, such as Notch, Wnt/ß-catenin, transforming growth factor-ß, and mitogen-activated protein kinase pathways. One novel group of molecules that have been shown to be inducted in the regulation of multiple cell signaling pathways is the long noncoding RNAs (lncRNAs). These molecules have important implications in the regulation of multiple signaling pathways by interacting with various genes, affecting the transcription process, and finally, playing roles in posttranslational control of these genes. There is growing evidence that lncRNAs are involved in the process of breast cancer formation by effecting the aforementioned signaling pathways, and that this involvement can have significant diagnostic and prognostic values in clinical contexts. The present review aims to elicit the significance of lncRNAs in the regulation of cell signaling pathways, and the resulting changes in cell survival, proliferation, and invasion, which are the hallmarks of breast cancer.

Overcoming multidrug resistance in cancer: Recent progress in nanotechnology and new horizons.

Multidrug resistance (MDR), defined as the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, is an important barrier in treating malignancies. Initially, it was discovered that cellular pumps dependent on ATP were the cause of resistance to chemotherapy, and further studies have found that other mechanisms such as increased metabolism of drugs, decreased drug entry, and defective apoptotic pathways are involved in this process. MDR has been the focus of numerous initiatives and countless studies have been undertaken to better understand MDR and formulate strategies to overcome its effects. The current review highlights various nano-drug delivery systems including polymeric/solid lipid/mesoporous silica/metal nanoparticles, dendrimers, liposomes, micelles, and nanostructured lipid carriers to overcome the mechanism of MDR. Nanoparticles are novel gateways to enhance the therapeutic efficacy of anticancer agents at the target site of action due to their tumor-targeting abilities, which can limit the unwanted systemic effects of chemotherapy agents and also reduce drug resistance. Additionally, other innovative strategies including RNA interference as a biological process used to inhibit or silence specific gene expression, natural products as MDR modulators with little systemic toxic effects, which interfere with the functions of proteins involved in drug efflux, and physical approaches such as combination of conventional drug administration with thermal/ultrasound/photodynamic strategies are also highlighted.

DNA damage response and repair in ovarian cancer: Potential targets for therapeutic strategies.

Ovarian cancer is among the most lethal gynecologic malignancies with a poor survival prognosis. The current therapeutic strategies involve surgery and chemotherapy. Research is now focused on novel agents especially those targeting DNA damage response (DDR) pathways. Understanding the DDR process in ovarian cancer necessitates having a detailed knowledge on a series of signaling mediators at the cellular and molecular levels. The complexity of the DDR process in ovarian cancer and how this process works in metastatic conditions is comprehensively reviewed. For evaluating the efficacy of therapeutic agents targeting DNA damage in ovarian cancer, we will discuss the components of this system including DDR sensors, DDR transducers, DDR mediators, and DDR effectors. The constituent pathways include DNA repair machinery, cell cycle checkpoints, and apoptotic pathways. We also will assess the potential of active mediators involved in the DDR process such as therapeutic and prognostic candidates that may facilitate future studies.

Melatonin-mediated regulation of autophagy: Making sense of double-edged sword in cancer.

Much research has been conducted to discover novel techniques to reverse the process of tumorigenesis and, cure already stablished malignancies. One well-stablished approach has been the use of organic compounds and naturally found agents such as melatonin whose anticancer effects have been shown in multiple studies, signaling a unique opportunity regarding cancer prevention and treatment. Various agents use a variety of methods to exert their anticancer effects. Two of the most important of these methods are interfering with cell signaling pathways and changing cellular functions, such as autophagy, which is essential in maintaining cellular stability against multiple exogenous and endogenous sources of stress, and is a major tool to evade early cell death. In this study, the importance of melatonin and autophagy are discussed, and the effects of melatonin on autophagy, and its contribution in the process of tumorigenesis are then noted.

53BP1: A key player of DNA damage response with critical functions in cancer.

Maintenance of genome integrity and stability is a critical responsibility of the DNA damage response (DDR) within cells, such that any disruption in this kinase-based signaling pathway leads to development of various disorders, particularly cancer. The tumor suppressor P53-binding protein 1 (53BP1), as one of the main mediators of DDR, plays a pivotal role in orchestrating the choice of double-strand break (DSB) repair pathway and contains interaction surfaces for numerous DSB-responsive proteins. It has been extensively demonstrated that aberrant expression of 53BP1 contributes to tumor occurrence and development. 53BP1 loss of function in tumor tissues is also related to tumor progression and poor prognosis in human malignancies. Due to undeniable importance of this protein in various aspects of cancer initiation/progression, angiogenesis, metastasis and development of drug resistance, as well as its targeting in the treatment of cancer, this review focused on explaining the structure and function of 53BP1 and its contribution to cancer.