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

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title
A membrane transporter determines the spectrum of activity of a potent platinum–acridine hybrid anticancer agent.
author
Bierbach, U.
author
Yao, X.
author
Watkins, N.
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.
subject
platinum–acridines
cancer
date
2021-03-22T13:23:38Z (accessioned)
2021-03-22T13:23:38Z (available)
2020-09-06 (issued)
identifier
Yao, X., Watkins, N.H., Brown-Harding, H. et al. A membrane transporter determines the spectrum of activity of a potent platinum–acridine hybrid anticancer agent. Sci Rep 10, 15201 (2020). https://doi.org/10.1038/s41598-020-72099-z (citation)
http://hdl.handle.net/10339/98585 (uri)
identifier
doi.org/10.1038/s41598-020-72099-z (doi)
language
en (iso)
publisher
SpringerNature
source
Scientific Reports
type
Article

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