nu-7441 and Neoplasms

Modulation of DNA repair pathways in oncology has been an area of intense interest in the last decade, not least as a consequence of the promising clinical activity of poly(ADP-ribose) polymerase (PARP) inhibitors. In this review article, we highlight inhibitors of the phosphatidylinositol 3-kinase related kinase (PIKK) family as of potential interest in the treatment of cancer, both in combination with DNA-damaging therapies and as stand-alone agents.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; DNA; DNA Repair; DNA-Activated Protein Kinase; DNA-Binding Proteins; Humans; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins

The AURKA gene encodes a protein kinase involved in cell cycle regulation and plays an oncogenic role in many cancers. The main objective of this study is to analyze AURKA expression in 13 common cancers and its role in prognostic and drug resistance.. Using the cancer genome atlas (TCGA) as well as CCLE and GDSC data, the level of AURKA gene expression and its role in prognosis and its association with drug resistance were evaluated, respectively. In addition, the expression level of AURKA was assessed in colorectal cancer (CRC) and gastric cancer (GC) samples. Besides, using Gene Expression Omnibus (GEO) data, drugs that could affect the expression level of this gene were also identified.. The results indicated that the expression level of AURKA gene in 13 common cancers increased significantly compared to normal samples or it survived poorly (HR >1, p < 0.01) in lung, prostate, kidney, bladder, and uterine cancers. Also, the gene expression data showed increased expression in CRC and GC samples compared to normal ones. The level of AURKA was significantly associated with the resistance to SB 505124, NU-7441, and irinotecan drugs (p < 0.01). Eventually, GEO data showed that JQ1, actinomycin D1, and camptothecin could reduce the expression of AURKA gene in different cancer cell lines (logFC < 1, p < 0.01).. Increased expression of AURKA is observed in prevalent cancers and associated with poor prognostic and the development of drug resistance. In addition, some chemotherapy drugs can reduce the expression of this gene.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aurora Kinase A; Azepines; Benzodioxoles; Biomarkers, Tumor; Camptothecin; Cell Line, Tumor; Chromones; Dactinomycin; Datasets as Topic; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Irinotecan; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Neoplasms; Prognosis; Pyridines; Triazoles

Monocyte-derived dendritic cell (moDC)-based cancer therapies intended to elicit antitumor T-cell responses have limited efficacy in most clinical trials. However, potent and sustained antitumor activity in a limited number of patients highlights the therapeutic potential of moDCs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cell Communication; Chromones; Dendritic Cells; Heterocyclic Compounds, 3-Ring; Humans; Lymphocyte Activation; Male; Mice; Morpholines; Neoplasms; Protein Kinase Inhibitors; T-Lymphocyte Subsets

A key modality of non-surgical cancer management is DNA damaging therapy that causes DNA double-strand breaks that are preferentially toxic to rapidly dividing cancer cells. Double-strand break repair capacity is recognized as an important mechanism in drug resistance and is therefore a potential target for adjuvant chemotherapy. Additionally, spontaneous and environmentally induced DSBs are known to promote cancer, making DSB evaluation important as a tool in epidemiology, clinical evaluation and in the development of novel pharmaceuticals. Currently available assays to detect double-strand breaks are limited in throughput and specificity and offer minimal information concerning the kinetics of repair. Here, we present the CometChip, a 96-well platform that enables assessment of double-strand break levels and repair capacity of multiple cell types and conditions in parallel and integrates with standard high-throughput screening and analysis technologies. We demonstrate the ability to detect multiple genetic deficiencies in double-strand break repair and evaluate a set of clinically relevant chemical inhibitors of one of the major double-strand break repair pathways, non-homologous end-joining. While other high-throughput repair assays measure residual damage or indirect markers of damage, the CometChip detects physical double-strand breaks, providing direct measurement of damage induction and repair capacity, which may be useful in developing and implementing treatment strategies with reduced side effects.

Topics: Animals; Cell Line; CHO Cells; Chromones; Cricetinae; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; DNA-Activated Protein Kinase; Drug Resistance, Neoplasm; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Morpholines; Neoplasms

Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can also be achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes (G4s) in cells and elicits a DNA damage response by causing the formation of DNA double strand breaks (DSB). Cell death mediated by ligand-induced G4 stabilization can be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrate that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for nonhomologous end joining repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair. G4 targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.

Topics: Aminoquinolines; Antineoplastic Agents; BRCA2 Protein; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromones; DNA Breaks; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G-Quadruplexes; Humans; Molecular Structure; Morpholines; Neoplasms; Picolinic Acids; Structure-Activity Relationship