Inhibition of the Wnt/b-catenin pathway using PNU-74654 reduces tumor growth in in vitro and in vivo models of colorectal cancer.

BACKGROUND: Colorectal-cancer (CRC) is amongst the most lethal-cancers, mainly due to its metastatic spread and drug chemoresistance. Hence there is a need for new approaches to either increase the efficacy of current therapy or introduce new therapies that have greater efficacy. There is increasing evidence that dysregulation of WNT-signaling-pathway plays an essential role in the development and prognosis of CRC. Here we have investigated the therapeutic potential of targeting the WNT/b-catenin pathway using a novel Wnt/b-catenin inhibitor, PNU-74654, in combination with 5-FU in CRC. METHODS: The anti-proliferative-effect of PNU-74654 was evaluated in two-/three-dimensional cell models. The activity of agents on cell growth, migration, invasion, cell cycle and apoptosis was evaluated by MTT, wound healing assay, invasion, FACS, and annexin V staining, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used a xenograft model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU follow by histological staining and biochemical and gene expression analyses by RT-PCR and western blot. RESULTS: PNU-74654 inhibited cell-growth and synergistically affected the anti-tumor properties of 5-FU via modulation of Cyclin D1 and survivin. This agent inhibited the migration/invasion of colorectal cancer cells via perturbation of E-cadherin. Furthermore, PNU-74654 inhibited the tumor growth, which was more pronounced using the PNU-74654 plus 5-FU combination via induction of reactive oxygen species, down-regulation of SOD and modulation of MCP-1, P53, TNF-α. CONCLUSIONS: Our finding demonstrated that PNU-74654 can target Wnt-pathway, interfere with cell-proliferation, induced-cell death, reduced-migration and interact with 5-FU, supporting further investigations on this therapeutic-approach for colorectal cancer.

The Role of Heat Shock Protein 40 in Carcinogenesis and Biology of Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Despite the enormous amount of effort in the diagnosis and treatment of CRC, the overall survival rate of patients remains low. The precise molecular and cellular basis underlying CRC has not been completely understood yet. Over time, new genes and molecular pathways involved in the pathogenesis of the disease are being identified. The accurate discovery of these genes and signaling pathways are important and urgent missions for the next generation of anticancer therapy research. Chaperone DnaJ, also known as Hsp40 (heat shock protein 40), has been of particular interest in CRC pathogenesis, as it is involved in the fundamental cell activities for maintaining cellular homeostasis. Evidence shows that protein family members of DnaJ/Hsp40 play both roles, enhancing and reducing the growth of CRC cells. In the present review, we focus on the current knowledge of the molecular mechanisms responsible for DnaJ/Hsp40 in CRC carcinogenesis and biology.

The Role of Heat Shock Protein 27 in Carcinogenesis and Treatment of Colorectal Cancer.

The incidence of colorectal cancer (CRC) has significantly increased in recent decades, which has made this disease an important global health issue. Despite many efforts, there is no useful prognostic or diagnostic biomarker for CRC. Heat shock protein 27 (Hsp27) is one of the most studied members of the Hsp family. It has attracted particular attention in CRC pathogenesis since it is involved in fundamental cell functions for cell survival. Evidence shows that Hsp27 plays important role in CRC progression and metastasis. Hsp27 overexpression has been observed in CRC and is suggested to be associated with CRC's poor prognosis. In the present review, we focus on the current knowledge of the role of Hsp27 in CRC carcinogenesis and the underlying mechanisms. In addition, we discuss the value of targeting Hsp27 in CRC treatment.

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway.

BACKGROUND: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. METHODS: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). RESULTS: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. CONCLUSION: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.

Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer.

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan's anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment.

Diabetes and COVID-19; a Review of Possible Mechanisms.

Coronavirus disease 2019 (SARS-CoV-2) (COVID-19) has recently raised worldwide public health concerns. The available data on COVID-19 in patients with diabetes is limited but generally indicate that there is an increased risk of developing COVID-19 infection in diabetic patients, which ultimately impacts the overall patient's survival. Various aspects might be involved; however, the exact mechanisms and interrelationships between diabetes and the novel COVID-19 have not yet been fully elucidated. This review summarizes the possible mechanisms by which present diabetes predispose individuals to COVID-19 infection, modulates the hostviral interactions and increases the risk of mortality. We hope this review can provide beneficial information for further studies and contribute to improved disease management of diabetic patients with COVID-19.

The hepatoprotective effects of fennel seeds extract and trans-Anethole in streptozotocin-induced liver injury in rats.

Hypoglycemic, anti-inflammatory, and antioxidant activities of fennel have been recorded in numerous investigations. The study aimed to evaluate the protective effects of fennel or its active component trans-Anethole (TA) on streptozotocin-induced liver injury in rats. Rats were injected with a single dose of STZ (65 mg/kg) and treated with fennel (200 and 400 mg/kg), TA (80 mg/kg), or metformin (300 mg/kg) for 35 days. Serum lipid profile and liver enzyme activity (aminotransferases), oxidative stress markers, and the degree of fibrosis in the liver tissue were assessed. Both fennel and TA decreased blood glucose levels, reduced liver enzyme activity, food, and water intake, and intensity of weight loss, reduced serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and increased high-density lipoprotein cholesterol (HDL-c). Additionally, fennel and TA significantly reduced MDA concentration while increased CAT activity and thiol content and reduced the degree of injury and fibrosis in the liver of diabetic rats. Our results suggest that fennel seed extract and its active compound TA are able to protect the liver against diabetes-induced hepatic injury in rats, probably via hypoglycemic and antioxidant effects.

The Clinical Impact of Quantitative Cell-free DNA, KRAS, and BRAF Mutations on Response to Anti-EGFR Treatment in Patients with Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common leading causes of cancer death in the world. Although EGFR inhibitors have established efficacy in metastatic colorectal cancer (mCRC), some patients do not respond to this treatment. The EGFR inhibitors' failure and acquired resistance are partly due to KRAS and BRAF mutations. Thus, prognostic biomarkers that help to select eligible patients are highly in demand. To improve patient selection, assessment of mutational status in circulating cell free DNA (cfDNA), which possibly represents the dynamicity of tumor genetic status better than tumor tissue, could be advantageous. This review summarizes the current knowledge of the prognostic value of cfDNA in patients with mCRC treated with EGFR inhibitors with emphasis on the clinical importance of identification of KRAS and BRAF mutations.

Crocin as a novel therapeutic agent against colitis.

Ulcerative colitis is a chronic inflammatory bowel disease with high incidence and prevalence worldwide. To investigate the therapeutic potency of crocin, as a pharmacologically active component of saffron, in dextran sodium sulfate (DSS)-induced colitis mice model. Experimental colitis was induced by 7-day administration of DSS dissolved in water at a concentration of 1.5% (w/v). The animals were randomly divided into four groups (n»6 for each group). (1) Control group received regular drinking water for four weeks, (2) the second group of mice received regular drinking water for three weeks and then received DSS for one week, (3) and (4) the other two groups received 50-ppm or 200-ppm crocin for three weeks, respectively, and then treated with DSS for one week. Our results showed that Crocin attenuates colitis disease activity index including body weight loss, diarrhea, rectal bleeding, and colon shortening in crocin pre-tread mice. Comparison of histology of colon tissues between groups showed that crocin significantly decreases colon histopathological score, at least partially, by eliciting anti-inflammatory responses in DSS-induced colitis mice. These results clearly showed that crocin is a novel therapeutic agent with low toxicity as well as great clinical significance in treatment of colitis.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as therapeutic options in the treatment of renal cancer: A meta-analysis.

AIMS: Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) which have been used in the treatment of cardiovascular diseases, have also been shown to have anti-tumor effects against various cancers that include renal cancer. The aim of current paper was to explore the potential clinical impact of ACEI/ARB inhibitors in renal cancer. MAIN METHODS: We used several databases: EMBASE, PubMed and the Cochrane library, to identify clinical studies that assessed the relationship between ACEIs/ARBs treatment and risk of renal cancer incidence or survival of renal cancer patients. The hazard ratio (HR) with 95% confidence intervals were obtained for assessing the relationship between ACEIs/ARBs and renal cancer mortality. KEY FINDING: The HR for the relationship between ASIs use and survival of renal cancer indicated that patients with renal cancer being treated with ACEIs/ARBs had a significantly lower mortality than non-user (HR 0.723, 95% CI 0.568-0.921, p = 0.009). The HR for the relationship between ACEIs use and survival of renal cancer indicated that patients with renal cancer that used ACEIs had a higher mortality than non-users (HR 1.352, 95% CI 0.917-1.991, p = 0.128). The HR for the relationship between ARBs use and survival of renal cancer indicated that patients with renal cancer that used ARBs had a decreased of mortality than non-users (HR 0.818, 95% CI 0.691-0.969, p = 0.02). SIGNIFICANCE: This meta-analysis demonstrated that treatment with ACEIs/ARBs may improve renal cancer survival and reduce the mortality of patients with renal cancer.

Losartan modulates brain inflammation and improves mood disorders and memory impairment induced by innate immune activation: The role of PPAR-γ activation.

In recent years, the role of angiotensin II (Ang II) and Ang II type 1 receptor (AT1) in the crosstalk between the immune system and the central nervous system has received more attention. The present study aimed to investigate the role of losartan, an AT1 receptor blocker, in the modulation of long-lasting adverse effects of repeated systemic lipopolysaccharide (LPS) injection in the brain function. For this purpose, 110 male BALB/c mice were administrated LPS (250 µg/kg) intraperitoneally (i.p.) for seven consecutive days. Mice were i.p. injected with losartan (1 and 3 mg/kg) three days before and during the LPS injection. To determine the role of PPAR-γ activation in the protective actions of losartan, GW9662, a PPAR-γ antagonist, was also co-administrated with losartan. Then, behavioral tests, including Morris water maze (MWM), novel object recognition test, passive avoidance, forced swim test (FST), elevated plus maze, and marble burying task, were conducted. The results demonstrated that losartan improved learning and memory impairment, attenuated anxiety-like behaviors, modulated brain inflammation and oxidative stress, and decreased amyloid-ß accumulation. Losartan was unable to improve hippocampal BDNF and IL-10 levels as well as the retention trial in the MWM task and depressive-like behaviors. In addition, the PPAR-γ antagonist did not significantly influence the beneficial effects of losartan. Our findings suggest that AT1R blockade can protect the brain against most long-lasting hallmark effects of systemic inflammation. Also, based on the results, the beneficial actions of losartan were not mediated through PPAR-γ activation.

Hsp70 inhibitors: Implications for the treatment of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in the world. Despite intensive advances in diagnosis and treatment of CRC, it is yet one of the leading cause of cancer related morbidity and mortality. Therefore, there is an urgent medical need for alternative therapeutic approaches to treat CRC. The 70 kDa heat shock proteins (Hsp70s) are a family of evolutionary conserved heat shock proteins, which play an important role in cell homeostasis and survival. They overexpress in various types of malignancy including CRC and are typically accompanied with poor prognosis. Hence, inhibition of Hsp70 may be considered as a striking chemotherapeutic avenue. This review summarizes the current knowledge on the progress made so far to discover compounds, which target the Hsp70 family, with particular emphasis on their efficacy in treatment of CRC. We also briefly explain the induction of Hsp70 as a strategy to prevent CRC.

MicroRNAs as potential therapeutic targets to predict responses to oxaliplatin in colorectal cancer: From basic evidence to therapeutic implication.

Colorectal cancer (CRC) is one of the most common malignancies with poor prognosis. Oxaliplatin-based chemotherapy is an important treatment for CRC; however, the cells develop resistance to therapy. The mechanisms underlying oxaliplatin resistance are complex and unclear. There is increasing evidence that microRNAs (miRNAs) (i.e., miR-34a, miR-143, miR-153, miR-27a, miR-218, and miR-520) play an essential role in tumorigenesis and chemotherapy resistance, by targeting various cellular and molecular pathways (i.e., PI3K/Akt/Wnt, EMT, p53, p21, and ATM) that are involved in the pathogenesis of CRC. Identifying the miRNAs that are involved in chemo-resistance, and their function, may help as a potential therapeutic option for treatment of CRC or as potential prognostic biomarker. Here, we summarized the clinical impact of miRNAs that have critical roles in the development of resistance to oxaliplatin in CRC.

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes.

Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concentration. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compounds, including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clinical trials investigation. In addition, other natural product-derived compounds have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compounds obtained from them, and discusses their application for the treatment of diabetes.

Therapeutic potential of toll-like receptors in treatment of gynecological cancers.

Toll-like receptors (TLRs) play an important role in the innate and adaptive immune system. They are expressed in various regions of the female reproductive tract, and their regulation may be involved in the pathogenesis of gynecological lesions. There is growing evidence that ligands for several TLRs are potentially anticancer agents, some of which have already been approved by the FDA, and these compounds are now undergoing clinical evaluation. There is a rationale for using these ligands as adjuvants in the treatment or prevention of gynecological cancer. Some TLR agonists that are of potential interest in the treatment of gynecological lesions include imiquimod, motolimod, cervarix, and CpG-oligodeoxynucleotides (ODNs). In this review, we outline the different functions of TLRs in gynecological cancer with particular emphasis on the value of TLR agonists as a potential therapeutic target in the treatment of gynecological cancer. © 2019 IUBMB Life, 71(5):549-564, 2019.

Reactive oxygen species in colorectal cancer: The therapeutic impact and its potential roles in tumor progression via perturbation of cellular and physiological dysregulated pathways.

Reactive oxygen species (ROS) are produced by mitochondria during metabolism. In physiological states, the production of ROS and their elimination by antioxidants are kept in balance. However, in pathological states, elevated levels of ROS interact with susceptible cellular target compounds including lipids, proteins, and DNA and deregulate oncogenic signaling pathways that are involved in colorectal cancer (CRC) carcinogenesis. Although antioxidant compounds have been successfully used in the treatment of CRC as prevention approaches, they have also been shown in some cases to promote disease progression. In this review, we focus on the role of ROS in gastrointestinal homeostasis, CRC progression, diagnosis, and therapy with particular emphasis on ROS-stimulated pathways.

Crocin synergistically enhances the antiproliferative activity of 5-flurouracil through Wnt/PI3K pathway in a mouse model of colitis-associated colorectal cancer.

Colorectal cancer (CRC) is the third most common cause of cancer-related death, and hence there is a need for the identification of novel-agents to improve the efficacy of existing therapies. There is growing evidence for the antitumor activity of crocin, although its activity and molecular mechanisms in CRC remains to be elucidated. Here we explored the therapeutic application of crocin or its combination with 5-flurouracil in a mouse model of colitis-associated colon cancer. The antiproliferative activity of crocin was assessed in two-dimensional and three-dimensional cell-culture models. The migratory behaviors were determined, while the expression levels of several genes were assessed by quantitative reverse transcriptase polymerase chain reaction/Western blot analysis. We examined the anti-inflammatory properties of crocin by pathological evaluation and disease-activity index as well as oxidative or antioxidant markers: malondialdehyde (MDA) and total-thiols (T-SH) levels and superoxide dismutase (SOD) and catalase (CAT) activity. Crocin suppressed cell-growth and the invasive behavior of CRC cells through modulation of the Wnt-pathway and E-cadherin. Moreover, administration of crocin alone, or in combination with 5-FU dramatically reduced the tumor number and tumor size in both distal/mid-colon followed by reduction in disease-activity index. Crocin also suppressed the colonic inflammation induced by dextran-sulfate-sodium and notably recovered the increased levels of MDA, decreased thiol levels and activity of CAT levels. Crocin was able to ameliorate the severe inflammation with mucosal ulcers and high-grade dysplastic crypts as detected by inflammation score, crypt loss, pathological changes and histology scores. We demonstrated an antitumor activity of crocin in CRC and its potential role in improvement of inflammation with mucosal ulcers and high-grade dysplastic crypts, supporting the desireability of further investigations on the therapeutic potential of this approach in CRC.

Pharmacogenetics of Anticancer Drug Sensitivity and Toxicity in Colorectal Cancer.

Inter-individual differences in drug response are an important cause of failure in anticancer treatment and adverse drug events in cancer patients. Gene polymorphisms related to these outcomes have been investigated in an effort to find new genetic biomarkers to predict toxicity and response to anticancer drugs. Evaluating the value single nucleotide polymorphisms (SNPs) in the genes involved in transportation, activation and metabolism of anticancer drugs provides a promising approach to select the appropriate therapeutic regimes with at least adverse reactions. This review summarizes the current knowledge about the relationship between of SNPs involved in the transportation, activation and metabolism of anticancer drugs and treatment outcomes in colorectal cancer (CRC) patients.

Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer.

Despite advances in the diagnosis and treatment of colorectal cancer (CRC), it remains a major cause of cancer related death globally. There are currently no chemotherapeutic agents that have been found to eradicate the disease without adverse effects. A defect in the death receptor signaling pathway is a feature of CRC. The ligand of these receptors belongs to the tumor necrosis factor family, and that are particularly expressed by cells of the immune system, and that induce apoptosis in a caspase dependent manner. The fact that malignant cells are particularly sensitive to these ligands, compared to normal cells, has led to work on the assessment of compounds that activate this pathway in the treatment of CRC. Phase I trials have shown that these death receptor agonists are safe. Phase II and III trials are currently investigating the efficacy of these therapeutic agents in the treatment of CRC. In this review, we describe the biochemical death receptor signaling pathway and its relationship to CRC. We also summarize the current clinical studies that are targeting this signaling pathway in CRC treatment.

Phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer.

Here we explored the antitumor-activity of novel-formulated-form of curcumin (phytosomal-encapsulated-curcumin) or in combination with 5-FU in breast cancer. The antiproliferative activity was assessed in 2D and 3-dimensional cell-culture-model. The migratory-behaviors of the cells were determined by migration assay. The expression levels of CyclinD1,GSK3a/b, P-AMPK, MMP9, and E-cadherin were studied by qRT-PCR and/or Western blotting. The anti-inflammatory of nano-curcumin was assessed, while antioxidant activity was evaluated by malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total thiols (T-SH). To understand dynamic behavior of genes, we reconstructed a Boolean network, while the robustness of this model was evaluated by Hamming distance. phytosomal-curcumin suppressed cell-growth followed by tumor-shrinkage in 3D model through perturbation of AMP-activated protein kinase. Curcumin reduced the invasiveness of MCF-7 through perturbation of E-cadherin. Moreover, phytosomal-curcumin inhibited the tumor growth in xerograph model. Histological staining of tumor tissues revealed vascular disruption and RBC extravasation, necrosis, tumor stroma, and inflammation. Co-treatment of curcumin and 5-FU reduced the lipid-peroxidation and increased MDA/SOD level. Of note, curcumin reduced cyclinD-expression in breast cancer cell treated with thrombin, and activates AMPK in a time-dependent manner. Also suppression of AMPK abrogated inhibitory effect of phytosomal-curcumin on thrombin-induced cyclin D1 over-expression, suggesting that AMPK is essential for anti-proliferative effect of this agent in breast cancer. Our finding demonstrated that phytosomal-curcumin antagonizes cell growth and migration, induced by thrombin through AMP-Kinase in breast cancer, supporting further-investigations on the therapeutic potential of this novel anticancer agent in treatment of breast cancer.