ME-344 [(3R,4S)-3,4-bis(4-hydroxyphenyl)-8-methyl-3,4-dihydro-2H-chromen-7-ol] is a second-generation derivative natural product isoflavone presently under clinical development. ME-344 effects were compared in lung cancer cell lines that are either intrinsically sensitive or resistant to the drug and in primary immortalized human lung embryonic fibroblasts (IHLEF). Cytotoxicity at low micromolar concentrations occurred only in sensitive cell lines, causing redox stress, decreased mitochondrial ATP production, and subsequent disruption of mitochondrial function. In a dose-dependent manner the drug caused instantaneous and pronounced inhibition of oxygen consumption rates (OCR) in drug-sensitive cells (quantitatively significantly less in drug-resistant cells). This was consistent with targeting of mitochondria by ME-344, with specific effects on the respiratory chain (resistance correlated with higher glycolytic indexes). OCR inhibition did not occur in primary IHLEF. ME-344 increased extracellular acidification rates in drug-resistant cells (significantly less in drug-sensitive cells), implying that ME-344 targets mitochondrial proton pumps. Only in drug-sensitive cells did ME-344 dose-dependently increase the intracellular generation of reactive oxygen species and cause oxidation of total (mainly glutathione) and protein thiols and the concomitant immediate increases in NADPH levels. We conclude that ME-344 causes complex, redox-specific, and mitochondria-targeted effects in lung cancer cells, which differ in extent from normal cells, correlate with drug sensitivity, and provide indications of a beneficial in vitro therapeutic index.
- Received September 15, 2015.
- Accepted May 26, 2016.
This work was supported by grants from the National Institutes of Health National Cancer Institute [Grants CA08660, CA117259] and National Center for Research Resources [Grant NCRR P20RR024485], COBRE in Oxidants, Redox Balance and Stress Signaling] and support from the South Carolina Centers of Excellence program and was conducted in a facility constructed with the support from the National Institutes of Health [Grant RR015455] from the Extramural Research Facilities Program of the National Center for Research Resources. C.D.B. and K.D.T. hold endowed Chairs from the South Carolina SmartState program. Supported in part by the Drug Metabolism and Clinical Pharmacology shared Resource, Hollings Cancer Center, Medical University of South Carolina. Further financial support was through an unrestricted grant from MEI Pharma Inc.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics