Following anticancer drug activity in cell lysates with DNA devices.

ABSTRACT: There is a great need to track the selectivity of anticancer drug activity and to understand the mechanisms of associated biological activity. Here we focus our studies on the specific NQO1 bioactivatable drug, ß-lapachone, which is in several Phase I clinical trials to treat human non-small cell lung, pancreatic and breast cancers. Multi-electrode chips with electrochemically-active DNA monolayers are used to track anticancer drug activity in cellular lysates and correlate cell death activity with DNA damage. Cells were prepared from the triple-negative breast cancer (TNBC) cell line, MDA-MB-231 (231) to be proficient or deficient in expression of the NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme, which is overexpressed in most solid cancers and lacking in control healthy cells. Cells were lysed and added to chips, and the impact of ?-lapachone (?-lap), an NQO1-dependent DNA-damaging drug, was tracked with DNA electrochemical signal changes arising from drug-induced DNA damage. Electrochemical DNA devices showed a 3.7-fold difference in the electrochemical responses in NQO1+ over NQO1- cell lysates, as well as 10-20-fold selectivity to catalase and dicoumarol controls that deactivate DNA damaging pathways. Concentration-dependence studies revealed that 1.4?µM ?-lap correlated with the onset of cell death from viability assays and the midpoint of DNA damage on the chip, and 2.5?µM ?-lap correlated with the midpoint of cell death and the saturation of DNA damage on the chip. Results indicate that these devices could inform therapeutic decisions for cancer treatment.

SUBMITTER: Kahanda D 

PROVIDER: S-EPMC6217983 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature