The relative importance of NADPH: cytochrome c (P450) reductase for determining the sensitivity of human tumour cells to the indolequinone EO9 and related analogues lacking functionality at the C-2 and C-3 positions.
Analogues of EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2[1H-indole-4-7-dione]prop-2-e n-1-ol) which lack functionality at either the C-2 or C-3 position were synthesised. The aim was to establish the importance of each group towards toxicity and to give an indication as to whether substitution at either position altered activation and toxicity after metabolism by cellular NADPH: cytochrome c (P450) reductase (P450R). MDA231 breast cancer cells were transfected with the cDNA for human P450R and stable clones were isolated. These high P450R-expressing clones were used to determine the aerobic and hypoxic toxicity of EO9 and the two analogues that lacked functionality at either C-2 or C-3. The results showed that P450R was strongly implicated in the bioactivation of EO9 and its analogues under both of these conditions. This data also showed that the C-3 functionality was primarily implicated in hypoxic toxicity.
Saunders
M P
MP
School of Pharmacy, University of Manchester, Manchester, UK.
Jaffar
M
M
Patterson
A V
AV
Nolan
J
J
Naylor
M A
MA
Phillips
R M
RM
Harris
A L
AL
Stratford
I J
IJ
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D009251:NADPH-Ferrihemoprotein Reductase; C060817:apaziquone