PNU-74654 enhances the antiproliferative effects of 5-FU in breast cancer and antagonizes thrombin-induced cell growth via the Wnt pathway

The Wnt/β-catenin pathway is one of the most common pathways dysregulated in breast cancer, and may, therefore, be a potential-therapeutic target. We have investigated the effects of PNU-74654 in breast cancer, as a Wnt/β-catenin inhibitor, either alone or in combination with fluorouracil (5-FU). PNU-74654 suppressed cell growth at an IC ₅₀ of 122 ± 0.4 μmol/L and synergistically enhanced the antiproliferative activity of gemcitabine by modulating the Wnt pathway. Using a 3D cell culture model, we found that the PNU-74654 caused tumor shrinkage. It reduced the migration of MCF-7 cells (by an 18% reduction in invasive behavior) after the treatment with PNU-74654 through perturbation of E-cadherin and MMP3/9. PNU-74654/5-FU combination enhanced the percentages of cells in S-phase and significantly increased apoptosis. Moreover, our data showed that this agent was able to inhibit the growth of tumor in a xenograft model, although this effect was more pronounced in the animals treated with PNU-74654 plus 5-FU. These data show the ability of PNU-74654 to specifically target Wnt pathway, interfere with cell proliferation, induce-apoptosis, reduce-migration, and synergistically interact with 5-FU, supporting further studies on this novel therapeutic-approach for breast cancer.     

The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives

Heat-shock protein 27 (HSP27) is a chaperone molecule that plays a critical role in the refolding and activity of several proteins responsible for cancer cell drug toxicity. Upregulation of HSP27 is associated with decreased drug sensitivity as well as poorer survival in gastrointestinal (GI) malignancies. It is, therefore, possible that HSP27 may be of value in the assessment of prognostic and therapeutic efficacy in the treatment of GI cancers. Pharmacological and biological inhibitors of HSP27 enhance tumor cell chemosensitivity. This review summarizes the potential role of HSP27 in chemotherapy drug resistance and the therapeutic potential of HSP27 inhibitors as a novel strategy in the treatment of GI cancers.     

Wnt pathway targeting reduces triple-negative breast cancer aggressiveness through miRNA regulation in vitro and in vivo

Triple-negative breast cancer, devoid of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is deprived of commonly used targeted therapies. MicroRNAs (miRNAs) are undergoing a revolution in terms of potentially diagnostic or therapeutic elements. Combining computational approaches, we enriched miRNA binding motifs of Wnt pathway-associated upregulated genes. Our in-depth bioinformatics, in vitro and in vivo analyses indicated that miR-381 targets main genes of the Wnt signaling pathway including CTNNB1, RhoA, ROCK1, and c-MYC genes. The expression level of miR-381 and target genes was assessed by quantitative real-time polymerase chain reaction (RT-qPCR) in MCF-7, MDA-MB-231, and MCF-10A as well as 20 breast cancer samples and normal tissues. Luciferase reporter assay was performed. Lentiviral particles containing miR-381 were used to evaluate the effect of miR-381 restoration on cell proliferation, migration, and invasion of the invasive triple-negative MDA-MB-231 cell line and also in a mouse model of breast cancer. The expression of miR-381 was lower than that of normal cells, especially in TNBC cell line and breast tissues. Luciferase assay results confirmed that miR-381 targets all the predicted 3′-untranslated regions (3′-UTRs). Upon miR-381 overexpression, the expression of target genes declined, and the migration and invasion potential of miR-381-receiving MDA-MB-231 cells decreased. In a mouse model of triple-negative breast cancer, miR-381 re-expression inhibited the invasion of cancer cells to lung and liver and prolonged the survival time of cancer cell-bearing mice. Therefore, miR-381 is a regulator of Wnt signaling and its re-expression provides a potentially effective strategy for inhibition of TNBC.     

Stem cell therapy: A novel approach for myocardial infarction

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Until recently, it was thought that myocardium was not able to repair itself, but studies have now shown that resident cardiac stem cells have regenerative capacity, and stem cell therapy may be a novel approach for cardiac muscle repair and regeneration. Stem cell-derived paracrine factors have been shown to regulate ventricular remodeling, inflammation, apoptosis, cardiomyocytes regeneration, and neovascularization in regions of infarcted cardiac tissue. In this review, we summarize the evidence from cellular, animal, and clinical studies supporting the potential clinical significance of stem cell therapy as a novel therapeutic approach for the treatment of MI.     

Survivin a pivotal antiapoptotic protein in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease, pathologically characterized by lymphocyte infiltration of the synovial membrane that leads to chronic inflammation and progressive joint damage. RA develops as a result of increased cell infiltration and cell proliferation as well as impaired cell death. Activated cells in joints including lymphocytes and fibroblast-like synoviocytes (FLS) survive for a long time as a consequence of compromised apoptosis, but the mechanism underlying cell survival in synovium remains to be firmly established. Inhibition of apoptosis by survivin, as a critical antiapoptotic protein, contributes to both the persistence of autoreactive T lymphocytes and tumor-like phenotype of FLS in RA. In addition to the antiapoptotic role, survivin also has prognostic relevance in RA prodromal phase. Hence, this review provides an overview of the current knowledge regarding the involvement of survivin protein in the pathogenesis of RA.     

Therapeutic potency of Wnt signaling antagonists in the pathogenesis of prostate cancer,current status and perspectives

Prostate cancer is a major cause of cancer-related death in males. Wnt/β-catenin signaling plays a critical role in the pathogenesis of this disease by regulating angiogenesis, drug resistance, cell proliferation, and apoptosis. Suppression of Wnt canonical or noncanonical signaling pathways via Wnt biological or pharmacological antagonists is a potentially novel therapeutic approach for patients with prostate cancer. This review summarizes the role of Wnt signaling inhibitors in the pathogenesis of prostate cancer for a better understanding and hence a better management of this disease.     

Hereditary breast cancer; Genetic penetrance and current status with BRCA

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.     

Trehalose administration attenuates atherosclerosis in rabbits fed a high-fat diet

Disruption of macrophage autophagy is a major contributor to macrophage dysfunction and subsequent inflammation leading to atherosclerosis. Trehalose is a natural disaccharide that is able to induce macrophage autophagy-lysosomal biogenesis and reduce inflammation. Here, we studied the efficacy of intravenous trehalose administration in reducing atherosclerotic plaque burden in high-cholesterol-fed rabbits. Adult male New Zealand white Rabbits were fed with a high-fat diet containing 1% cholesterol for 8 weeks followed by a cholesterol-free diet for the next 4 weeks. In the latter 4-week phase of the cholesterol-free diet, one group received intravenous trehalose solution at a dose of 350 mg/kg, three times per week. In the control group, an equivalent volume of PBS (3 mL) was administered with the same protocol. At the end of the 12th week of the study, all rabbits were anesthetized and aortic arch sections were collected followed by hematoxylin and eosin staining and assessment of plaque grading. Fasting serum lipids were also measured using routine enzymatic methods. At the end of the 12th week, there were no significant differences in the body weight and blood lipids between the control- and trehalose-treated groups. Intravenous trehalose administration significantly attenuated atherosclerotic plaque development as revealed by reduced plaque grading ( P = 0.048) and intima/media thickness ratio ( P = 0.017). Intimal thickening was also found to be reduced in the trehalose versus control group, though this reduction did not reach statistical significance. The present study provided evidence as to the efficacy of short-term intravenous trehalose administration in regressing atherosclerotic plaque in high-fat-fed rabbits.     

TWIST1, MMP-21, and HLAG-1 co-overexpression is associated with ESCC aggressiveness

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive types of cancer, requiring reliable biomarkers for prognosis and therapeutic responsiveness. TWIST1, as an important factor responsible for metastasis of several cancers, is involved in tumor invasion and metastasis through indirectly regulation of MMP-21 expression. On the other hand, NF-ĸβ which is a regulator of HLAG-1 has direct interaction with TWIST1 protein. In this retrospective study we investigated the clinical significance of TWIST1, MMP-21, and HLAG-1 expression in ESCC, and the possible correlation between these genes and progression of the disease. The gene expression analyses of TWIST1, MMP-21, and HLA-G1 were performed by relative comparative real-time polymerase chain reaction in 58 ESCCs compared with corresponding margin-normal esophageal tissues. Significant overexpression of HLAG-1, TWIST1, and MMP-21 messenger RNA was observed in 22.4%, 41.4%, and 60.3% of tumor samples, respectively. Concomitant overexpression of TWIST1/MMP-21 and TWIST1/HLAG-1 were significantly correlated to each other in various clinicopathological features, including depth of tumor invasion, stage of tumor progression, lymphatic invasion, and grade of tumor cell differentiation ( P < 0.05). The current study is the first report of coexpression of TWIST1, MMP-21, and HLAG-1 in ESCC. Such findings suggest an oncogenic role for concomitant expression of these genes in ESCC invasion and metastasis.     

The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.