Abstract
Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation.
Highlights
Doxorubicin (Adriamycin, Dox) is an antibiotic anthracycline that is used frequently in chemotherapy for a variety of solid tumors and leukemias [1,2,3]
Recent reports point to the critical role of metabolism in determining cell sensitivity to doxorubicin, a conventional drug used in leukemia treatment
Most of the molecular components involved in doxorubicin metabolism have been identified; how these components operate as a system and how adaptation of the doxorubicin metabolic network to patient-specific changes in protein components is much less understood
Summary
Doxorubicin (Adriamycin, Dox) is an antibiotic anthracycline that is used frequently in chemotherapy for a variety of solid tumors and leukemias [1,2,3]. Because the modulation of Pgp activity in vivo [8,9] and the use of antioxidants [11,12] have failed to demonstrate any long term disease-free survival, alternative mechanisms have been proposed to describe the antitumor effects of doxorubicin and thereby offer plausible explanations for why some cancers are sensitive to doxorubicin treatment while others are not To this end, the reductive conversion of doxorubicin has been implicated as a major determinant of doxorubicin cytotoxicity and has been proposed as an underlying factor controlling drug resistance in cancer cells [3,4,5,13]. While it is widely accepted that CPR is the primary enzyme for catalyzing the reductive conversion of doxorubicin in vivo [17,19], overexpression of CPR does not result in enhanced doxorubicin cytotoxicity [16]
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