Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress

Abstract

Doxorubicin (also called Adriamycin) is effective in treating a wide range of human cancers and currently considered as one of the most important drugs in cancer chemotherapeutics. The clinical use of doxorubicin is, however, associated with dosage-dependent cardiotoxicity and development of heart failure, which diminish the therapeutic index of this widely used anticancer drug. This article first surveys key research findings on doxorubicin redox biology that may impact its cardiotoxicity as well as anticancer activity. It then discusses emerging concepts, especially the topoisomerase IIb-p53-mitochondrion axis that may lead to the development of mechanistically based novel strategies to protect against cardiotoxicity and enhance the effectiveness of doxorubicin therapy.

Keywords: Anticancer drug; Doxorubicin; Mitochondrial electron transport chain; Oxidative stress; Reactive oxygen species; Redox biology; Redox cycling; Topoisomerase IIb.

FIGURE 1. Schematic illustration of the general concept of quinone redox cycling

As depicted, the cytochrome P450 (CYP) system and the mitochondrial electron transport chain (METC) are the two major machineries that carry out the initial one-electron reduction of quinone compounds, leading to redox cycling and generation of superoxide anion radical (O₂^•−). O₂^{• −} undergoes dismutation to form hydrogen peroxide either spontaneously or catalyzed by superoxide dismutase (SOD). Hydrogen peroxide then reacts with transition metal ion (e.g., Fe²⁺, Cu¹⁺), giving rise to hydroxyl radical (not shown).

FIGURE 2. Schematic illustration of the potential of doxorubicin to undergo redox cycling catalyzed by the cytochrome P450 system (CYP450) and mitochondrial electron transport chain (METC)

As illustrated, doxorubicin contains a p-benzoquinone structure. p-Benzoquinone is actually a weak, if not a non-, redox cycling compound.

FIGURE 3. Schematic illustration of the potential role of the topoisomerase IIb–p53–mitochondrion axis in doxorubicin cardiotoxicity

DOX, doxorubicin; Top-IIb, topoisomerase IIb; PGC1α, peroxisome proliferator-activated receptor gamma co-activator 1α; PGC1β, peroxisome proliferator-activated receptor gamma co-activator 1b; ROS, reactive oxygen species. This scheme is based on Ref. [28].

FIGURE 4. Schematic illustration of the potential involvement of the doxorubicin-topoisomerase IIb complex in transcriptional repression of PGC1α and PGC1β, leading to mitochondrial dysfunction, decreased antioxidant expression, and oxidative stress, and ultimately cardiac cell injury

DOX, doxorubicin; Top-IIb, topoisomerase IIb; PGC1α, peroxisome proliferator-activated receptor gamma co-activator 1α; PGC1β, peroxisome proliferator-activated receptor gamma co-activator 1b; ROS, reactive oxygen species. This scheme is based on Ref. [27].