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.     

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.     

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.     

The role of microRNAs involved in PI3-kinase signaling pathway in colorectal cancer

In recent decades, cancer has been one of the most important concerns of the human community, which affects human life from many different ways, such as breast, lung, colorectal, prostate, and other cancers. Colorectal cancer is one of the most commonly diagnosed cancers in the world that has recently been introduced as the third leading cause of cancer deaths in the world. microRNAs have a very crucial role in tumorgenesis and prevention of cancer, which plays a significant role with influencing various factors through different signaling pathways. Phosphoinositide 3 (PI3)-kinase/AKT is one of the most important signaling pathways involved in the control and growth of tumor in colorectal cancer, through important proteins of this pathway, such as PTEN and AKT, that they can perform specific influence on this process. Our effort in this study is to collect microRNAs that act as tumor suppressors and oncomirs in this cancer through PI3-kinase/AKT signaling pathway.     

Toll-like receptors signaling network in pre-eclampsia: An updated review

Toll-like receptors (TLRs) are innate immune cells receptors. They are expressed on leukocytes, epithelial cells, and more particularly on placental immune cells and chorion trophoblast. Upregulation of innate immune response occurs during normal pregnancy, but its excessive activity is involved in the pathology of pregnancy complications including pregnancy-induced hypertension and pre-eclampsia (PE). The recent studies about the overmuch inflammatory responses and aberrant placentation are associated with increased expression of TLRs in PE patients. This review has tried to focus on the relationship between some activities of TLRs and the risk of preeclampsia development.     

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT₁) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT₁ receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.     

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.