A membrane transporter determines the spectrum of activity of a potent platinum-acridine hybrid anticancer agent.

Abstract

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 < 10-5) 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.

• Authors: Xiyuan Yao, Noah H Watkins, Heather Brown-Harding, Ulrich Bierbach
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 15201 (09 16 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32939009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Acridines
• Antineoplastic Agents
• Benzamides
• Biphenyl Compounds
• EED226
• Morpholines
• Organic Cation Transport Proteins
• Organoplatinum Compounds
• Pyridones
• SLC47A1 protein, human
• Sulfones
• Triazoles
• Platinum
• tazemetostat
• Pyrimethamine

Topics

• A549 Cells
• Acridines (chemistry)
• Antineoplastic Agents (chemistry, pharmacology)
• Benzamides (pharmacology)
• Biphenyl Compounds
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• Epigenesis, Genetic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Molecular Structure
• Morpholines
• Organic Cation Transport Proteins (genetics)
• Organoplatinum Compounds (chemistry, pharmacology)
• Platinum (chemistry)
• Pyridones (pharmacology)
• Pyrimethamine (pharmacology)
• Sulfones (pharmacology)
• Triazoles (pharmacology)