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submitted on 04.06.2020 and posted on 05.06.2020by 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