Efficient hypoxic activation of the anticancer agent AQ4N by CYP2S1 and CYP2W1.
AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in solid tumors. CYP2S1 and CYP2W1, two extrahepatic P450 enzymes identified from the human genome whose functions are unknown, are expressed in hypoxic tumor cells at much higher levels than in normal tissue. Here, we demonstrate that CYP2S1, contrary to a published report (Mol Pharmacol 76:1031-1043, 2009), is efficiently reduced by NADPH-P450 reductase. Most importantly, both CYP2S1 and CYP2W1 are better catalysts for the reductive activation of AQ4N to AQ4 than all previously examined P450 enzymes. The overexpression of CYP2S1 and CYP2W1 in tumor tissues, together with their high catalytic activities for AQ4N activation, suggests that they may be exploited for the localized activation of anticancer prodrugs.
Nishida
Clinton R
CR
Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158-2517, USA.
Lee
Melody
M
de Montellano
Paul R Ortiz
PR
D000880:Anthraquinones; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D000860:Hypoxia; D009251:NADPH-Ferrihemoprotein Reductase; D009369:Neoplasms / Q000188:drug therapy; D010087:Oxides / Q000627:therapeutic use; D011355:Prodrugs / Q000627:therapeutic use
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010087:Oxides; D011355:Prodrugs; C094428:AQ4N; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase