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A Membrane Transporter Determines the Spectrum of Activity of a Potent DNA-Targeted Hybrid Anticancer Agent

preprint
submitted on 04.06.2020, 21:29 and posted on 05.06.2020, 13:19 by Xiyuan Yao, Noah Watkins, Heather Brown-Harding, Ulrich Bierbach
Cytotoxic drugs that are mechanistically distinct from current chemotherapies are attractive components of personalized combination regimens for combating aggressive forms of cancer. To gain insight into the cellular mechanism of a highly potent platinum–acridine hybrid agent, we performed a correlation analysis of NCI-60 compound screening results and gene expression profiles. We discovered a plasma membrane transporter, human multidrug and toxin extrusion protein 1 (hMATE1, SLC47A1), as the dominant pan-cancer predictor for cancer cell chemosensitivity to the hybrid agent. We have validated the role of hMATE1 using transporter inhibition, gene knockdown, and chemical sensitization assays. The results suggest that hMATE1 may have applications as a molecular marker to identify and target tumors that are likely to respond to platinum–acridines. Furthermore, enhancement of hMATE1 expression by epigenetic drugs emerges as a potential co-treatment strategy to sensitize tumor tissue to platinum–acridines and other anticancer drugs transported by hMATE1.

History

Email Address of Submitting Author

bierbau@wfu.edu

Institution

Wake Forest University

Country

United States

ORCID For Submitting Author

0000-0001-5658-7662

Declaration of Conflict of Interest

no conflict of interest

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