A membrane transporter determines the spectrum of activity of a potent platinum-acridine hybrid anticancer agent
| Autor: | Ulrich Bierbach, Noah H. Watkins, Xiyuan Yao, Heather Brown-Harding |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
SLC47A1 Organic Cation Transport Proteins Organoplatinum Compounds Cell Survival Pyridones Morpholines lcsh:Medicine Antineoplastic Agents Article Bioinorganic chemistry Target validation Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Target identification Cytotoxic T cell Humans Drug discovery and development Viability assay Sulfones lcsh:Science Cell Proliferation Platinum Gene knockdown Multidisciplinary biology Molecular Structure Chemistry lcsh:R Biphenyl Compounds Transporter Drug Synergism Triazoles HCT116 Cells Solute carrier family Gene Expression Regulation Neoplastic 030104 developmental biology Pyrimethamine A549 Cells 030220 oncology & carcinogenesis Cancer cell Benzamides Screening biology.protein Cancer research Acridines lcsh:Q Intracellular |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-11 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Cytotoxic drugs that are mechanistically distinct from current chemotherapies are attractive components of personalized combination regimens for combatting aggressive forms of cancer. To gain insight into the cellular mechanism of a potent platinum–acridine anticancer agent (compound 1), a correlation analysis of NCI-60 compound screening results and gene expression profiles was performed. A plasma membrane transporter, the solute carrier (SLC) human multidrug and toxin extrusion protein 1 (hMATE1, SLC47A1), emerged as the dominant predictor of cancer cell chemosensitivity to the hybrid agent (Pearson correlation analysis, p –5) across a wide range of tissues of origin. The crucial role of hMATE1 was validated in lung adenocarcinoma cells (A549), which expresses high levels of the membrane transporter, using transporter inhibition assays and transient knockdown of the SLC47A1 gene, in conjunction with quantification of intracellular accumulation of compound 1 and cell viability screening. Preliminary data also show that HCT-116 colon cancer cells, in which hMATE1 is epigenetically repressed, can be sensitized to compound 1 by priming the cells with the drugs EPZ-6438 (tazemetostat) and EED226. Collectively, these results suggest that hMATE1 may have applications as a pan-cancer molecular marker to identify and target tumors that are likely to respond to platinum–acridines. |
| Databáze: | OpenAIRE |
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