Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.

Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioblastoma stem cells (GSCs) not only initiate and sustain uncontrolled cell proliferation but also resistant to conventional clinical therapies including temozolomide (TMZ) dependent chemotherapy and radiotherapy, implying that there is an urgent need to identify new therapeutic strategies especially specific targeting GSCs. Here, we provide evidence showing that ivacaftor commonly applied in cystic fibrosis therapy acts as a potent inhibitor for GSCs maintenance. We found that ivacaftor promotes cellular apoptosis in vitro and represses patient-derived xenograft (PDX) tumor growth in vivo. In addition, we demonstrate that ivacaftor decreases stemness marker gene expressions of GSCs, including CD133, CD44, and Sox2. In summary, our findings reveal that ivacaftor inhibits glioblastoma progression via specifically eliminating GSCs, which opens a new avenue for GBM clinical therapy in the future.

Identification of Novel Inhibitors of GLUT1 by Virtual Screening and Cell-Based Assays

In order to fuel the uncontrolled cell proliferation and division, tumor cells reprogram the energy metabolism to Warburg effect, where glucose is favorite converted by glycolysis even in the presence of oxygen. However, the high energetic demand of tumor cells require upregulating the expression of glucose transporters, notably GLUT1, which substantially increases glucose uptake into cytoplasm. GLUT1 is overexpressed in a variety of tumor cells and is likely to be a potential drug target for the pan-cancer treatment. Although many small molecules were reported to inhibit theglucose uptake function by various measurements, several shortcomings such as weak binding affinity, low specificity of the known inhibitors demand the identification of alternative inhibitors with novel scaffolds. In this study, we performed a virtual screening campaign by docking each compound from Chemdiv database to the glucosebinding pocket based on the crystal structure of GLUT1 (PDB ID 4PYP) and four small molecules with novel scaffolds were identified to inhibit the glucose uptake of cancer cells at the sub-micromole levels. The identified compounds may serve as starting points for the development of anti-cancer drugs by manipulating the energy metabolism.

Protein phase separation and its role in tumorigenesis

Cancer is a disease characterized by uncontrolled cell proliferation, but the precise pathological mechanisms underlying tumorigenesis often remain to be elucidated. In recent years, condensates formed by phase separation have emerged as a new principle governing the organization and functional regulation of cells. Increasing evidence links cancer-related mutations to aberrantly altered condensate assembly, suggesting that condensates play a key role in tumorigenesis. In this review, we summarize and discuss the latest progress on the formation, regulation, and function of condensates. Special emphasis is given to emerging evidence regarding the link between condensates and the initiation and progression of cancers.

Tyrosine Kinase Inhibitors (TKIs) in Lung Cancer Treatment: a Comprehensive Analysis

: Lung cancer is the leading type of cancer worldwide today. Kinases play a crucial role in mediating the signaling pathways and it directs to control several necessary cellular processes. Conversely, deregulation of tyrosine kinases leads to oncogenic conversion, uncontrolled cell proliferation and tumorigenesis. Tyrosine kinases are largely deregulated in lung cancer and specifically in non-small cell lung cancer (NSCLC). Therefore the inhibition of pathogenic kinases is a breakthrough development in cancer research, treatment and care, which clinically improves the quality of life. In the last decades various single or combination inhibitors are approved by U.S Food and Drug Administration (FDA) and commercially available in clinics, and currently several preclinical studies are ongoing and examining the kinase inhibitors. However, many gaps remains in understanding of the mechanisms of kinase inhibitors and their selectivity. In this analysis, we focus on a class of receptor and non-receptor tyrosine kinase inhibitors and their novel role in lung cancer.

Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation

Somatic mutations in the RAS genes are frequent in human tumors, especially in pancreatic, colorectal, and non-small-cell lung cancers. Such mutations generally decrease the ability of Ras to hydrolyze GTP, maintaining the protein in a constitutively active GTP-bound form that drives uncontrolled cell proliferation. Efforts to develop drugs that target Ras oncoproteins have been unsuccessful. Recent emerging data suggest that Ras regulation is more complex than the scientific community has believed for decades. In this review, we summarize advances in the “textbook” view of Ras activation. We also discuss a novel type of Ras regulation that involves direct phosphorylation and dephosphorylation of Ras tyrosine residues. The discovery that pharmacological inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras in an inactive state suggests that SHP2 could be a novel drug target for the treatment of Ras-driven human cancers.

A Systematic Review and Bioinformatics Study on Genes and micro-RNAs Involving the Transformation of Endometriosis into Ovarian Cancer

Background: Along with the description of tumorigenesis processes in endometriosisrelated ovarian cancer, identifying dysregulated miRNAs, the target genes of these miRNAs, and the processes abnormally affected by dysregulated miRNAs is essential, which was our goal. Methods: Two reviewers individually evaluated the articles which collected relevant information including genes and miRNAs involved in the transformation of endometriosis into ovarian cancer. To assess the mature sequence of miRNAs and also their chromosomal positions, miRPathDB software was employed. To determine the main target gene predicted for each considered miRNAs, the TargetScanS Web server was applied. The interaction of each gene with other genes associated with endometrial- related ovarian cancer was determined by GeneMANIA software. Finally, to design integrated model of miRNAs-targeted genes interaction network, the Cytoscape software was used. Results: The final number of studies available for analysis was 6 manuscripts including 22 miRNAs described as involved in the transformation of endometriosis into different subtypes of ovarian cancers (14 miRNAs up-regulated and 8 miRNAs down-regulated). Three miRNAs of miR-141 (upregulated), miR-205 (down-regulated), and miR-125b (down-regulated) were revealed as the originator for genetic interactions leading to carcinogenesis. We could show some common loops and pathways including uncontrolled cell proliferation and abnormal apoptosis (mediated by PTEN gene induced by miR-21 and miR-214), and disaggregation and epithelialization (mediated by ZEB1 and ZEB2 genes induced by miR-200). Conclusions: According to our analysis, up-regulation of miR-141 and down-regulation of miR-205 and miR-125b have a central role in transforming endometriosis to ovarian cancer.

Tumor Microenvironment

Background and Objectives: The tumor microenvironment has been widely implicated in tumorigenesis because it harbors tumor cells that interact with surrounding cells through the circulatory and lymphatic systems to influence the development and progression of cancer. In addition, nonmalignant cells in the tumor microenvironment play critical roles in all the stages of carcinogenesis by stimulating and facilitating uncontrolled cell proliferation. Aim: This study aims to explore the concept of the tumor microenvironment by conducting a critical review of previous studies on the topic. Materials and Methods: This review relies on evidence presented in previous studies related to the topic. The articles included in this review were obtained from different medical and health databases. Results and Discussion: The tumor microenvironment has received significant attention in the cancer literature, with a particular focus on its role in tumor development and progression. Previous studies have identified various components of the tumor microenvironment that influence malignant behavior and progression. In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells. Conclusion: The tumor microenvironment harbors cancer stem cells and other molecules that contribute to tumor development and progression. Consequently, targeting and manipulating the cells and factors in the tumor microenvironment during cancer treatment can help control malignancies and achieve positive health outcomes.

Interplay between miRNAs and Genes Associated with Cell Proliferation in Endometrial Cancer

Endometrial cancer develops as a result of abnormal cell growth associated with uncontrolled cell proliferation, excessive activation of signaling pathways and miRNA activity. The aim of this study was to determine the expression profile of genes associated with cell proliferation and to assess which miRNAs can participate in the regulation of their expression. The study enrolled 40 patients with endometrial cancer and 10 patients without neoplastic changes. The expression profile of genes associated with cell proliferation and the expression profile of miRNAs were assessed using microarrays. RT-qPCR was performed to validate mRNA microarray results. The mirTAR tool was used to identify miRNAs that regulate the activity of genes associated with cell proliferation. Decreased expression of IGF1 and MYLK, as well as SOD2 overexpression, were observed in endometrial cancer using both mRNA microarrays and RT-qPCR. Microarray analysis showed low levels of NES and PRKCA, but this was only partially validated using RT-qPCR. Reduced activity of MYLK may be caused by increased miR-200c, miR-155 and miR-200b expression. Cell proliferation is disturbed in endometrial cancer, which may be associated with an overexpression of miR-200a, miR-200c, and miR-155, making it a potential diagnostic marker.

Evaluation of Cancer Incidence and Age-adjusted in Regional Cancer Center of Tamilnadu Districts by using Mathematical Technique

he term cancer does not stand for a single disease, but represents a collection of diseases characterized by uncontrolled cell proliferation. Now a days cancer is one of the main disease to affect the human beings. Due to this is causes death. It is a challenging one to the society for their health problem. The main objective is to explore the design and trends of the cancer incidence in location of the nine regional cancer centers and cancer treatment facilities in the area. (ie., Coimbatore, Kanniyakumari, Salem, Thanjavur, Tirunelveli, Madurai, Trichy, Chennai, Kanchipuram).The cancer cases were separated district wise regional cancer centers for specific cancer sites and age-standardized incident rates were calculated for females. By using Mathematical Technique we found to the cancer incidence and age adjusted of cancer. ie) which district wise regional cancer centers higher in the cancer incidence and age adjusted and which district wise regional cancer centers least in the cancer incidence and age adjusted ?vvvv