title: Cytotoxicity of a novel indoloquinone eo9 in hypoxic non-small-cell lung-cancer cell-lines.
abstract: 3-Hydroxymethyl-5-aziridinyl-1-methyl-[1H-indole-4,7-dione]-prop-beta-en -alpha-ol (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and structurally related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of EO9 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to EO9 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC50 value of PC-9 against EO9 was significantly increased by co-incubation with dicumarol under oxic conditions. EO9 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempol under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of EO9 under hypoxic conditions and EO9 may be more active against oxygen-deficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity.
authors.forename: T
authors.initials: T
authors.lastname: Bando
authors.forename: K
authors.initials: K
authors.lastname: Kasahara
authors.forename: K
authors.initials: K
authors.lastname: Shibata
authors.forename: Y
authors.initials: Y
authors.lastname: Numata
authors.forename: U
authors.initials: U
authors.lastname: Heki
authors.forename: H
authors.initials: H
authors.lastname: Shirasaki
authors.forename: K
authors.initials: K
authors.lastname: Iwasa
authors.forename: M
authors.initials: M
authors.lastname: Fujimura
authors.forename: T
authors.initials: T
authors.lastname: Matsuda