The kinetics and redox state of nitric oxide determine the biological consequences in lung adenocarcinoma.
Few studies have explored the mechanistic basis for the apparent paradoxical effects of nitric oxide and its interrelated redox species (NO(X)) in cancer biology. Our aim was to determine the differential effects of the redox state and kinetics of nitrosative species on the key cancer processes of apoptosis. Therefore, a murine lung adenocarcinoma cell line was exposed to various NO(X) donor compounds differing in redox state and delivery kinetics. DNA strand breaks (DSBs) were measured by the alkaline single-cell gel electrophoresis assay (the COMET assay) and correlated with cell viability by the MTT and soft agar colony assays, while caspase enzymatic activity was measured using an in vitro fluorogenic caspase assay. Finally, cDNA microarrays defined apoptosis-related gene expression alterations resultant from these NO(X) donors. Exogenous NO(X) differentially influences DSBs, and apoptosis-related cell death and expression based on the redox state and kinetics of NO(X) delivery. In our murine lung adenocarcinoma model we have demonstrated differential effects of NO(X) based on the mode of delivery and redox state. These data suggest that the development of NO(X)-based cancer chemotherapy must consider the redox state and kinetics of delivery into their logical design.
Bentz
Brandon G
BG
Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Utah, Salt Lake City, Utah 84132, USA. brandon.bentz@hci.utah.edu
Hammer
Neal D
ND
Milash
Brett
B
Klein
Slobodanka
S
Burnett
David M
DM
Radosevich
James A
JA
Haines
G Kenneth
GK
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003114:Colony-Forming Units Assay; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D007700:Kinetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D020030:Nitric Oxide Donors; D009573:Nitrites; D012333:RNA, Messenger; D009569:Nitric Oxide; D020169:Caspases