adenanthin and Neoplasms

Target-based screening and cell-based screening are major approaches to identify anticancer drug candidates. Cell-based screening often contributes to the discovery of first-in-class drugs, but identification of the cellular targets of obtained compounds is a time-consuming step. To overcome this problem, affinity purification with small-molecule probes, which is a classic, but still the most common approach, has become more sophisticated and diversified. In addition, recent advances in omics studies and imaging analyses have allowed us to profile the biological effects of small molecules globally and quantitatively. Consequently, new therapeutic targets/drug leads involved in cancer cell cycle, transcription and redox regulation have been discovered.

Topics: Aminoquinolines; Antineoplastic Agents; Carbamates; Cell Cycle; Coumarins; Diamines; Diterpenes, Kaurane; Drug Discovery; Humans; Molecular Targeted Therapy; Neoplasms; Pyrazoles; Quinolines

Natural killer (NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin 1 (PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease.

Topics: Antibody-Dependent Cell Cytotoxicity; Antioxidants; Cell Degranulation; Cell Line, Tumor; Diterpenes, Kaurane; Enzyme Inhibitors; Glutathione; Humans; Killer Cells, Natural; Neoplasms; Oxidative Stress; Peroxiredoxins; Reactive Oxygen Species; Thioredoxin Reductase 1; Thioredoxins