TY - JOUR
T1 - Induction of cell death by a novel naphthoquinone containing a modified anthracycline ring system
AU - Carvajal, Denisse
AU - Kennedy, Steven
AU - Boustani, Andre
AU - Lazar, Monica
AU - Nguyen, Suong
AU - Dicesare, John C.
AU - Sheaff, Robert J.
PY - 2011/11
Y1 - 2011/11
N2 - The novel naphthoquinone adduct 12,13-Dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized as a potential chemotherapeutic agent. TU100 arrests tissue culture cells in S and G2/M phases of the cell cycle, followed by rapid induction of apoptosis. Evaluation by the Developmental Therapeutics Program at the National Cancer Institute revealed TU100 differentially inhibits growth of tissue-specific human cancer cell lines and has in vivo efficacy in a hollow fiber assay. These data were evaluated against previously analyzed compounds using the COMPARE algorithm and predicted that TU100 has a unique mechanism of action. Further analysis revealed TU100 does not intercalate into DNA despite structural similarity to anthracyclines. Cells treated with the drug do exhibit DNA damage, however, as indicated by phosphorylation of histone H2A.X. This damage and effects on cell viability are likely mediated in part by TU100-induced reactive oxygen species. Based on these results, TU100 shows promise as a chemotherapeutic drug owing to its unique structure, cellular targets, and efficacy against selected panels of tissue-specific cancer cell lines.
AB - The novel naphthoquinone adduct 12,13-Dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized as a potential chemotherapeutic agent. TU100 arrests tissue culture cells in S and G2/M phases of the cell cycle, followed by rapid induction of apoptosis. Evaluation by the Developmental Therapeutics Program at the National Cancer Institute revealed TU100 differentially inhibits growth of tissue-specific human cancer cell lines and has in vivo efficacy in a hollow fiber assay. These data were evaluated against previously analyzed compounds using the COMPARE algorithm and predicted that TU100 has a unique mechanism of action. Further analysis revealed TU100 does not intercalate into DNA despite structural similarity to anthracyclines. Cells treated with the drug do exhibit DNA damage, however, as indicated by phosphorylation of histone H2A.X. This damage and effects on cell viability are likely mediated in part by TU100-induced reactive oxygen species. Based on these results, TU100 shows promise as a chemotherapeutic drug owing to its unique structure, cellular targets, and efficacy against selected panels of tissue-specific cancer cell lines.
KW - Anthracycline
KW - Apoptosis
KW - Chemotherapeutic
KW - DNA damage
KW - Isoquinoline
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=80054104926&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2011.01214.x
DO - 10.1111/j.1747-0285.2011.01214.x
M3 - Article
C2 - 21838760
AN - SCOPUS:80054104926
SN - 1747-0277
VL - 78
SP - 764
EP - 777
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 5
ER -