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

The clinical impact of exosomes in cardiovascular disorders: from basic science to clinical application

Cardiovascular disease (CVD) is the major cause of death globally; therefore, there is a need for the identification of valid biomarker that accurately predict the risk of developing cardiovascular disease, and novel therapeutic approaches for its treatment. Exosomes are very small extracellular vesicles containing protein, lipid, transcription factors, mRNAs, non-coding RNA and nucleic acid contents, that are important players in intercellular communication, and that act via long-range signals or cell-to-cell contact. The discovery of exosomes provides potential strategies for the diagnosis and treatment of cardiovascular disease. In the current review, we have explored the potential impact of exosomes on cardiovascular physiology, and their therapeutic potential in cardiovascular disorders with a emphasize on the existing preclinical studies

Toll-like receptors signaling pathways as a potential therapeutic target in cardiovascular disease

Cardiovascular disease (CVD) is one of the most important causes of morbidity and mortality, and associated with an important economic burden globally. Over the last decade, the prevalence of CVD has been rising globally, and is now associated with millions of death annually in both developed and developing countries. There is good evidence that the immune system is involved in the pathophysiology of CVD. Toll-like receptors (TLRs) and their down-stream signaling pathways play an important role in the immune system. Recent studies have suggested that the TLRs are involved in atherogenesis, including stroke, myocardial infarction, ischemia-reperfusion injury, cardiac remodeling and development of heart failure (HF). In this review we have summarized the recent studies investigating the role of TLRs in CVD and the potential for using TLRs signaling pathways as a therapeutic target in CVD

Epigenetic drug therapy in the treatment of colorectal cancer

Colorectal cancer (CRC) is one of the most common cancers with a high rate of morbidity and mortality worldwide. The incidence of CRC is similar in men and women but is distributed uniformly globally. It has been demonstrated that epigenetic alterations which may cause changes in the expression of microRNA, DNA methylation and histone acetylation that results in inheritable modifications in gene expression in colorectal epithelial cells, plays a crucial role in the development of CRC. Recently, targeting epigenetic modification has emerged as a potentially important treatment approach in CRC. The US Food and Drug Association has approved the use of some epigenetic drugs that may be able to inhibit or reverse these alterations and also enhance sensitivity to chemotherapeutic agents and radiotherapy in CRC. In this review we have summarized the recent pre-clinical and clinical trial studies investigating the therapeutic value of using epigenetic drugs as novel therapeutic approach in CRC treatment. Keywords: epigenetic, colorectal cancer, drug, DNA methylation, histone acetylatio

The therapeutic potential of losartan in lung metastasis of colorectal cancer

Colorectal cancer (CRC) is a common cancer with a high incidence rate. Components of the renin-angiotensin system (RAS) have been reported to be dysregulated in several malignancies including CRC. Here, we have explored the potential anti-metastatic effects of a RAS inhibitor, losartan, in an experimental model of lung metastasis in CRC. A murine model of lung metastasis of CRC was used, which involved the intravenous injection of CT26 cells via a tail vein. Four experimental groups comprised: an untreated group; a group that received 5-FU which was administered intraperitoneally; a losartan group that received a combination group that received 5-FU plus losartan . We evaluated the anti-inflammatory effects of losartan by histopathological method, and the measurement of oxidative or antioxidant markers including malondialdehyde (MDA) and total-thiols (T-SH) tissue levels, superoxide-dismutase (SOD) and catalase activity. We found that losartan inhibited lung metastasis of CRC and there was a reduction of the IL-6 expression level in the tissue sample. It was also associated with reduced levels of the anti-angiogenic factor Vascular endothelial growth factor (VEGF). Furthermore, we found that losartan induced oxidative stress as assessed by an elevation of MDA level, reduction of T-SH, SOD and catalase activities in lung tissue. Our findings demonstrated that losartan ameliorates angiogenesis, inflammation and the induction of oxidative stress via Angiotensin II type I receptor (AT1R). This may shine some lights on targeting the RAS pathway as a potential therapeutic approach in the treatment of metastatic CRC patients

The prognostic value of cyclin D1 expression in the survival of cancer patients: a meta-analysis

Background The relationship between the expression of cyclin D1 and cancer prognosis and outcomes in different malignancies has not been fully elucidated. Aims In the presented meta-analysis, we assessed the association between the expression level of cyclin D1 with overall survival (OS) in several cancers. Methods Eligible studies were identified using PubMed, EMBase, Scopus, Web of Sciences and Cochrane Library databases. For the prognostic meta-analysis, study-specific hazard ratios (HRs) of tissue cyclin D1 for survival were obtained. Finally we pooled data derived from one hundred and eight studies comprising 19,224 patients with 10 different cancer types. Results In the pooled analysis, high expression of cyclin D1 was significantly related to a poor OS with a pooled HR of 1.11 (95% CI: 1.02–1.20, P = 0.015; random-effects). Sub-group analysis revealed that high expression of cyclin D1 was related to worse OS of head and neck cancers (HR = 2.08, 95% CI: 1.75–2.47; P < 0.001), but not in breast (HR = 1.033, 95% CI: 0.873–1.223, P = 0.702), gastrointestinal (HR = 1.025, 95% CI:0.824–1.275; P = 0.825), bladder (HR = 0.937, CI: 0.844–1.041; P = 0.225) and in lung cancer patients (HR = 1.092, CI: 0.819–1.455; P = 0.549). Conclusion Further large, prospective, and well-designed trials are warranted to elucidate the precise clinical importance of cyclin D1 overexpression in the prognosis of cancer patients receiving different treatment regimens

Association between non-alcoholic fatty liver disease and colorectal cancer

Introduction: Colorectal cancer (CRC) is a common malignancy and ranking fourth among the causes of cancer-related deaths globally. Its incidence has increased in recent decades, and now more than one million CRC patients are diagnosed and thousands die annually. The 5-year survival rate varies with the stage at diagnosis, being approximately 90% in the early stages of disease, and less than 10% in advanced disease. Nonalcoholic fatty liver disease (NAFLD), which is a major cause of chronic liver disease, and characterized by the accumulation of fat in hepatocytes, has also emerged as a risk factor for CRC, and to be related with the development of colorectal polyps. Areas covered: The purpose of this current review is to summarize the main findings of studies that have investigated the role of NAFLD in development of CRC. Expert commentary: Various molecular pathways, are altered during the development of NAFLD, which are also important in CRC tumorigenesis. There is growing body of evidence showing the potential role of activation of pro-inflammatory, disruption of antiinflammatory pathways, increasing the activity of pathways involved in cell proliferation/survival. Thus targeting these deregulated pathways via novel inhibitors can be a potential therapy for CRC prevention in cases with NAFLD

The impact of statin therapy on the survival of patients with gastrointestinal cancer

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins effect several potential pathways, including: cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website clinicaltrials.gov. Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting. However, randomized controlled trials on specific cancer types in relation to statin use, as well as studies on populations without a clinical indication for using statins, have elucidated some potential underlying biological mechanisms, and the investigation of different statins is probably warranted. It would be useful for these trials to incorporate the assessment of tumour biomarkers predictive of statin response in their design. This review summarizes the recent preclinical and clinical studies that assess the application of statins in the treatment of gastrointestinal cancers with particular emphasize on their association with cancer risk

Prognostic value of high mobility group protein A2 (HMGA2) over-expression in cancer progression

The high mobility group A2 (HMGA2; also called HMGI-C) gene is an architectural transcription factor that belonging to the high mobility group AT-hook (HMGA) gene family. HMGA2 is aberrantly regulated in several human tumors. Over-expression of HMGA2 is correlated with a higher risk of metastasis and an unfavorable prognosis in patients with cancer. We performed a meta-analysis to determine the clinic-pathological and prognostic value of HMGA2 overexpression in different human tumors. A comprehensive literature search was performed using PubMed, Embase, Cochrane Library, Scopus, MEDLINE, Google Scholar and ISI Web of Science. Hazard ratios (HRs)/odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of the association between HMGA2 expression and overall survival (OS)/progression free survival (PFS)/disease free survival (DFS). A total of 5319 patients with 19 different types of cancer from 35 articles were evaluated. Pooled data analysis indicated that increased HMGA2 expression in cancer patients predicted a poor OS (HR = 1.70; 95% CI = 1.6–1.81; P < 0.001; fixed-effect model). In subgroup analyses, high HMGA2 expression was particularly associated with poor OS in individuals with gastrointestinal (GI) cancer (HR = 1.89, 95% CI: 1.83–1.96; fixed-effect model) and HNSCC cancer (HR-1.78, 95%CI: 1.44–2.21; fixed-effect model). Over-expression of HMGA2 was associated with vascular invasion (OR = 0.16, 95% CI = 0.05–0.49; P = 0.001) and lymphatic invasion (OR = 1.89, 95% CI = 1.06–3.38; P = 0.032). Further studies should be conducted to validate the prognostic value of HMGA2 for patients with GI cancers