Critical Reviews in Oncogenesis最新文献

Investigating factors for childhood malignancies is distinctly more difficult than doing so for adults, as childhood exposure to environmental stimuli, occupational hazards, and age-related geriatric risks is less prevalent. A synergistic approach involving surgical intervention, chemotherapy, and radiation therapy has been the "gold standard treatment" for combating childhood malignancies. Nevertheless, these strategies are associated with various side effects, with nonspecific cytotoxicity being the major setback observed in patients under therapy. For this reason, hardcore intense chemotherapy for pediatric malignancies has remained a "Pandora's box" in cancer management. Understanding the mechanisms behind immune surveillance of tumors, immune escape mechanisms, and antitumor immune responses has enabled the development of novel methods and approaches in pediatric cancer therapy. This review will focus on the potential of immunotherapy in combating pediatric cancers, available strategies, and limitations of current approaches.

This article provides a basic summary of computational research on benzimidazole and its molecular targets in breast cancer (BC) drug discovery. The drug development process is streamlined, expenses are decreased, and the possibility of finding successful therapies for this difficult illness is increased with the use of computational tools. The utilization of benzimidazole derivatives in medication research and discovery is discussed, along with the results of benzimidazole derivative-related clinical trials conducted against blood cancer during the previous five years. Additionally, it includes analysis of changes in structure and how they affect pharmacology. The structure-based method and other computational tools used in drug development are also covered, as well as the importance of structural information such as stereochemistry, physiological action, and the use of spectroscopic methods like NMR and X-ray crystallography in understanding the interactions between bioactive compounds and receptors. The article highlights the potential of benzimidazoles as bioactive heterocyclic molecules with various biological activities, including antimicrobial and anti-cancer properties.

Nucleolar-spindle-associated protein 1 (NUSAP1) participates in the assembly of microtubules and the mitotic spindle. Mitotic spindles are microtubule-based structures that segregate chromosomes during mitosis. Its overexpression and knockdown caused alterations in gene expression programs linked to tumor progression. It was also identified as one of the potential hub genes in various cancers, including the mediation of hepatocellular carcinoma. The present research addresses the NUSAP1 protein structure refinement and its targeting by the lead molecules identified using various computational approaches. The initial structure of NUSAP1 from the Alpha fold database is evaluated using the Ramachandran plot and subjected to multiple energy minimization steps through the YASARA program. The best-optimized structure of NUSAP1 is obtained and subjected to binding site analysis and virtual screening studies using I-TASSER and Mcule webservers, respectively. From the binding site analysis, His293 was considered the ligand binding site for docking ligands by AutoDock Vina. Selected ligands from the Mcule chemical library were chosen through various filters, and 50 hits were identified for further studies. Among the 50 hits, 27 were identified as non-toxic molecules using a toxicity checker. Further, based on the RO5 violation check, 18 hits exhibited no RO5 violations. Further, for all 18 hits, LigPlot analysis was performed, and 11 hits exhibited hydrogen and hydrophobic interactions with the NUSAP1 protein. Among 11, three hits showed promising hydrogen and hydrophobic interactions near the potential binding site His293. For the promising three hits with Mcule IDs 9300000909-0-6, 9753624331-0-3, and 1764527053-0-4, ADMET properties were predicted using the PreADMET server. The comparative studies of drug-likeness properties found that all three hits do not violate Lipinski's rule of 5. The comparative studies of ADME properties of three hits found that the 9753624331-0-3 compound exhibits non-inhibiting properties in liver enzymes and p-glycoprotein inhibition. Furthermore, 9753624331-0-3 is computed as the lowest solvation-free energy of -18.1300000 and found to be non-mutagenic, negative for all toxicity studies, including the Ames test, fishes, rats, mice, and daphnia. Based on the drug-likeness, ADME, and toxicity predictions, the 9753624331-0-3 presented favorable properties and hence may be considered the potential lead targeting the NUSAP1 protein.

Colon cancer (CC) is the 3rd most prevalent cancer globally, following breast and lung cancer, with the second-highest mortality rate. Multiple risk factors contribute to CC, and metastasis is the primary cause of increased mortality among CC patients. Natural compounds have been investigated for their ability to concurrently influence various carcinogenic mechanisms by interfering with the expression or activity of their signaling targets. This review focuses on natural flavonoids such as quercetin, taxifolin, and rutin. We discuss how these bioactive compounds potentially mitigate metastasis and associated signaling pathways in colon cancer.

Tumor-associated macrophages (TAMs) are the predominant cell infiltrate in the immunosuppressive tumor microenvironment (TME). TAMs are central to fostering pro-inflammatory conditions, tumor growth, metastasis, and inhibiting therapy responses. Many cancer patients are innately refractory to chemotherapy and or develop resistance following initial treatments. There is a clinical correlation between the level of TAMs in the TME and chemoresistance. Hence, the pivotal role of TAMs in contributing to chemoresistance has garnered significant attention toward targeting TAMs to reverse this resistance. A prerequisite for such an approach requires a thorough understanding of the various underlying mechanisms by which TAMs inhibit response to chemotherapeutic drugs. Such mechanisms include enhancing drug efflux, regulating drug metabolism and detoxification, supporting cancer stem cell (CSCs) resistance, promoting epithelial-mesenchymal transition (EMT), inhibiting drug penetration and its metabolism, stimulating angiogenesis, impacting inhibitory STAT3/NF-κB survival pathways, and releasing specific inhibitory cytokines including TGF-β and IL-10. Accordingly, several strategies have been developed to overcome TAM-modulated chemoresistance. These include novel therapies that aim to deplete TAMs, repolarize them toward the anti-tumor M1-like phenotype, or block recruitment of monocytes into the TME. Current results from TAM-targeted treatments have been unimpressive; however, the use of TAM-targeted therapies in combination appears promising These include targeting TAMs with radiotherapy, chemotherapy, chemokine receptor inhibitors, immunotherapy, and loaded nanoparticles. The clinical limitations of these strategies are discussed.

The current rapid development of more selective and effective drugs for the treatment of thyroid cancer has open a new era in the treatment of patients with this condition, in the past limited to the possibility of only radioactive iodine for well differentiated tumor and surgery for medullary thyroid carcinoma (MTC). The treatment of advanced medullary thyroid carcinoma has evolved in the last few years and options for patients with advanced disease are now available. Multikinase inhibitors (MKIs) with nonselective RET inhibition like Vandetanib and Cabozantinib were approved for the treatment of MTC, although the efficacy is limited due to the lack of specificity resulting in a higher rate of drug-related adverse events, leading to subsequent dose reductions, or discontinuation, and the development of a resistance mechanism like seen on the RET Val804 gatekeeper mutations. MTC is associated with mutations in the RET protooncogene, and new highly selective RET inhibitors have been developed including Selpercatinib and Pralsetinib, drugs that have demonstrate excellent results in clinical trials, and efficacy even in the presence of gatekeeper mutations. However, despite their efficacy and great tolerability, mechanisms of resistance have been described, such as the RET solvent front mutations. Due to this, the need of constant evolution and drug research is necessary to overcome the emergence of resistance mechanisms.