Critical Reviews in Oncogenesis最新文献

Acute lymphoblastic leukemia (ALL) is a common pediatric cancer marked by uncontrolled proliferation of lymphoblasts, primarily affecting children aged two to five years. While treatment success rates have reached 90% in children, challenges such as therapy toxicity and relapse persist. The gut microbiome, known to impact immune function, is often disrupted in ALL patients, potentially worsening with treatments like chemotherapy and antibiotics. Research suggests probiotics may help restore microbial balance and mitigate side effects, with certain strains showing promise in reducing gastrointestinal symptoms; however, their use requires caution in immunocompromised patients due to infection risks. Probiotics could improve treatment outcomes in ALL, but further research is needed to establish safe, standardized protocols for use in this sensitive population.

Key molecular pathways involved in colorectal cancer (CRC) progression include the activation of the heat shock protein 90 (HSP90) pathway, PI3K/AKT, TP53, and mismatch repair (MMR) pathways. In the current study, we identified that FKBP4 is overexpressed at the transcript and translational levels in CRC patient samples, suggesting it may be a predictive biomarker for diagnosis. Our STRING network data analysis identified a strong association (string score: 0.999) between FKBP4 and HSP90. HSP90 is involved in stability, transportation, and protein folding. TCGA CRC patient samples data revealed a strong positive correlation between FKBP4 and HSP90. Furthermore, molecular docking, dynamics simulations, and hydrogen bond analysis confirmed a strong interaction between FKBP4 and HSP90, suggesting its importance in CRC cell survival and progression. These findings highlight that disrupting the FKBP4-HSP90 complex could be a promising therapeutic approach for CRC.

Molecular docking is a structure-based computational technique that plays a major role in drug discovery. Molecular docking enhances the efficacy of determining the metabolic interaction between two molecules, i.e., the small molecule (ligand) and the target molecule (protein), to find the best orientation of a ligand to its target molecule with minimal free energy in forming a stable complex. By stimulating drug-target interactions, docking helps identify small molecules that might inhibit cancer-promoting proteins, aiding in the development of novel targeted therapies. Molecular docking enables researchers to screen vast reorganization, identifying potential anti-cancer drugs with enhanced specificity and reduced toxicity. The growing importance of molecular docking underscores its potential to revolutionize cancer treatment by accelerating the identification of novel drugs and improving clinical outcomes. As a wide approach, this computational drug design technique can be considered more effective and timesaving than other cancer treatment methods. In this review, we showcase brief information on the role of molecular docking and its importance in cancer research for drug discovery and target identification. Therefore, in recent years, it can be concluded that molecular docking can be scrutinized as one of the novel strategies at the leading edge of cancer-targeting drug discovery.

Colorectal cancer (CRC) initiates in colon or rectum is named as colon or rectal cancer, based on the site of inception. Various genetic alterations responsible for CRC include several signaling pathways. The Wingless/Wnt signaling pathway is the vital pathway which involved in the cancer pathogenesis. The hallmark of human CRC is adenomatous polyposis coli (APC), a negative regulator of the Wnt pathway. Mutations in the APC gene is a critical event in the development of human CRC which may lead to overexpression and stabilization of β-catenin that enters into the nucleus and helps in cancer cell proliferation. Significant obstacles to the therapeutic intervention of the Wnt signaling system still exist, despite promising approaches for the development of anti-cancer medicines targeting this route. The advent of computational techniques for cancer diagnosis, prognosis, and drug development has spurred the researchers to explore CRC at an early stage. This report had unzipped the importance of APC in Wnt signaling pathway associated with current advances and challenges in drug discovery for CRC. A combinatorial computational approach identified the potential anti-cancerous drug among XL888, 5-bromouracil, 5-fluorouracil, and Ganetespib against APC which is often treated as gatekeeper of CRC. This in silico investigation revealed Ganetespib as a potential anti-cancerous drug against APC for CRC therapeutics, which will be an alternative to chemotherapy. In vitro and in vivo studies are needed further to confirm the efficiency and evaluate potency of Ganetespib against the target.

Millions of women worldwide have breast cancer, a common and possibly fatal illness according to WHO Reports. A genetic mutation usually causes breast adenocarcinomas. Only 5-10% of cancers are induced by genetic mutations that develop with age, and the "wear and tear" of general life causes 85-90% of breast cancers. There are not many FDA-approved treatments available on the market right now, but those that have extreme toxicity and side effects restrict their use. Consequently, it is essential to use alternative medications to prevent breast cancer. The Grangea maderaspatana plant has a variety of natural chemicals that have been selected for their therapeutic characteristics. These properties include cytotoxicity, antispasmodic, anti-inflammatory, sedative, anti-flatulent, antipyretic, antidiarrheal, antioxidant, estrogenicity, and anti-implantation activity. The whole plant has been used in folk medicine since the classical era to treat an assortment of illnesses. However, using molecular docking, we evaluated the interactions between the natural substances of Grangea maderaspatana and the breast adenocarcinoma receptor (PDB-1M17). Two reference medications, anastrozole and tamoxifen, are utilized to investigate drug similarity and comparability. The compound - (-) Frullanolide has showed aromatase inhibitor (estrogen blocker) efficacy as tamoxifen and anastrozole, which is utilized in the treatment of breast cancer. Given their favorable pharmacokinetics (ADMET) characteristics, the majority of these substances show promise as therapeutic candidates for breast adenocarcinoma. The findings from this research could aid in the development of new and efficient treatment options for breast cancer, potentially improving patient outcomes and standards of living.

Immunogenic cell death (ICD) is a regulated form of cell death that elicits an adaptive immune response, recognized as a promising strategy in cancer immunotherapy. Its therapeutic efficacy, however, can be influenced by tumor-intrinsic factors, particularly in heterogeneous diseases like breast cancer (BC). This study investigated the ICD-related gene expression signature in BC using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) cohorts. Analysis revealed significantly elevated expression of HSP90AA1, CXCR3, MYD88, FOXP3, PDIA3, XBP1, and IFNB1, and reduced expression of P2RX7 in BC tissues compared with normal tissues. Furthermore, the expression of these genes varied significantly across distinct BC subtypes, patient ages, and tumor stages. Concurrently, an investigation into the UPR pathway, known to intersect with ICD, highlighted Binding immunoglobulin Protein (BiP/GRP78/HSPA5) as a molecule of interest. To explore potential modulators of this pathway, in silico docking studies were performed, which predicted favorable binding interactions of quercetin and taxifolin with BiP. These findings suggest that characterizing the expression patterns of these ICD-related genes and UPR components could inform the development of personalized immunotherapeutic strategies for BC, tailored to specific tumor subtypes, stages, and patient demographics. Further exploration of BiP's role and its potential for therapeutic manipulation may offer novel avenues to enhance anti-tumor immunity.

Bacteria, fungi, and algae are examples of microorganisms that synthesize polysaccharides, which are macromolecules that belong to the carbohydrate class. Production of polysaccharides represents an alternative to chemical and plant-derived compounds that could be used for human well-being which requires implementation of different methods standardized during the extraction and purification process. In the current investigation, Pseudolagarobasidium acaciicola, a novel fungal source of exopolysaccharide (EPS) was used which produced 2773.23 ± 100.39 mg/L when cultured under pre-optimized composed medium for 7 days under submerged culture conditions. Biochemical estimation of crude polysaccharides revealed the presence of carbohydrates, protein, reducing sugar, least phenolics and no flavonoids. Partially purified EPS (ppEPS) was subjected to monosaccharide analysis, molecular weight determination and structural confirmation using FTIR and LCMS analysis. The presence of maltose, fructose, xylose, galactose, glucose, raffinose and sorbose was evident in the ppEPS using HPTLC at 285 nm, with molecular weight of dextran 70 (tentative). Characterization revealed the presence of functional groups including -OH, -COO, C-O-C and C-O with compounds like cellulose, phosphate and 3'-Sialyl-N-acetyllactosamine with glycan as the main structural form. Hence, our hypothesis is: the fungal strain may be used as a novel source of glycan and explore more possibilities for enhanced recovery of EPS important for further drug discovery and formulation programs. Based on existing research on the anti-cancerous characteristics of β-Glycans, an in silico study was carried out, which suggested that β-Glycans may operate more potent against its receptor CLEC7A than the oral chemotherapy drug imatinib.

Coralyne (COR) is a protoberberine-like isoquinoline alkaloid, and it is known for double-stranded (ds) DNA intercalation and topoisomerase inhibition. It can also sensitize cancer cells through various mechanisms. COR reduces the proliferation and migration of breast cancer cells by inhibiting the expression and activity of matrix metalloproteinase 9 (MMP9). However, the mechanism involved in the inhibitory activity of COR on MMP9 is not known. In the present study, in silico docking studies showed that COR binds to the active site of MMP9 catalytic domain (MMP9-CD) with considerable affinity. The binding affinity of COR to the MMP9-CD, estimated by three different web servers: CB Dock, Seam Dock, and PyRx, was found to be either -7.4 or -7.5 kcal/mol. Another web server that is routinely used for docking studies, Docking Server, has predicted a binding affinity of -5.9 kcal/mol. All four docking servers predicted the same binding site for COR within the MMP9-CD. Corroborating our docking results, molecular dynamic simulation studies have also shown that COR interacts with the same key active site amino acid residues of the MMP9-CD that are essential for its proteolytic function. Molecular mechanics with generalized born and surface area (MMGBSA) calculations using Schrodinger's prime module have shown that the binding free energy with which COR binds to MMP9 is -50 kcal/mol. It inhibited activity of recombinant human MMP9 activity and induced significant cytotoxicity and reduced the proliferation of MDA-MB 468 cells. Overall, our in silico and in vitro experiments show that COR potentially inhibits the activity of MMP9 by directly binding to the active site of its catalytic domain and possibly inhibits proliferation of MDA-MB 468 cells.

The c-Jun N-terminal protein kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family. JNK1, JNK2, and JNK3 are three isoforms encoded by distinct genes. JNK signaling controls a variety of biological functions, such as cell proliferation, survival, apoptosis, and differentiation. Additionally, it controls the death and survival of cancer cells. Many studies show that JNK-driven tumorigenesis plays a major role in various cancers. Because JNKs are potential targets for cancer therapy since they are activated aberrantly in many cancers, the development of efficient and specific JNK inhibitors is the current focus in cancer therapeutics. This review provides insights into the development of new JNK inhibitors for the treatment of cancer and enhances understanding of JNK's involvement in cancer progression.

The gut microbiota is integral to human health, influencing nutrition, metabolism, and immunity. Dysbiosis has been implicated in cancer development and resistance to therapies, highlighting the potential of microbiota modulation as a therapeutic strategy. Melanoma, while comprising only 1% of skin cancer diagnoses, accounts for over 80% of skin cancer related deaths, emphasizing the need for innovative approaches to enhance treatment efficacy. Although immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockade therapies have significantly improved survival for some melanoma patients, the majority fails to achieve durable responses and often develops long-term resistance to these treatments. Fecal microbiota transplantation (FMT) is emerging as a promising intervention to restore microbial balance and enhance treatment efficacy. This review explores the historical evolution and current applications of FMT in oncology, with a focus on its ability to modulate the gut microbiome, augment antitumor immunity, and overcome resistance to checkpoint blockade therapy in melanoma. Despite its promise, significant challenges remain, including ensuring the safety of the procedure, selecting suitable donors, and addressing regulatory hurdles. Future research aimed at optimizing FMT protocols, identifying key microbial strains, and understanding the mechanisms underlying microbiota-immune interactions will be essential to fully harness the potential of FMT as a transformative adjunct in cancer treatment.