Mechanism of Action of Anthracyclines
Anthracyclines exert their antitumor activity through multiple interconnected mechanisms: intercalation into nuclear DNA, inhibition of topoisomerase II, generation of reactive oxygen species (ROS), and disruption of cell membranes and mitochondria. 1
Primary Antitumor Mechanisms
DNA intercalation occurs when anthracycline molecules insert between DNA base pairs, physically disrupting the double helix structure and interfering with DNA replication and transcription 1
Topoisomerase II inhibition is a critical mechanism—anthracyclines stabilize the topoisomerase II-DNA complex, preventing the enzyme from religating cleaved DNA strands, which leads to DNA breaks and triggers apoptosis 1
Reactive oxygen species generation occurs through two pathways: formation of anthracycline-iron complexes and redox cycling of the quinone and semiquinone moieties of the drug molecule 1
Direct membrane disruption affects both cell membranes and mitochondrial membranes, contributing to cellular dysfunction 1
Cardiotoxicity Mechanisms (Distinct from Antitumor Effects)
The mechanisms responsible for cardiac toxicity appear to be separate from those causing antitumor activity, which explains why cardioprotective strategies don't necessarily reduce anticancer efficacy 1
Oxidative Stress Pathway
ROS-mediated myocyte injury is the major contributor to anthracycline cardiotoxicity—highly reactive oxygen species (hydrogen peroxide, hydroxyl radicals) are toxic to cardiac myocytes 1
Limited antioxidant defenses make myocytes particularly vulnerable—cardiac cells have low concentrations of the antioxidant enzyme catalase compared to other tissues 1
Suppression of protective enzymes occurs as anthracyclines inhibit myocardial glutathione oxidase, further reducing the heart's ability to neutralize ROS 1
Lipid peroxidation and membrane damage result when ROS interact with cellular components, directly injuring myocyte membranes 1
Activation of apoptotic pathways occurs through oxidant stress triggering MAPK (mitogen-activated protein kinase) and SAPK (stress-activated protein kinase) pathways that modulate programmed cell death 1
Mitochondrial Dysfunction
Cardiolipin binding is a critical mechanism—doxorubicin binds to cardiolipin, a phospholipid essential for maintaining respiratory chain function in mitochondria 1
Respiratory chain suppression occurs through direct inhibition of mitochondrial respiratory chain activity, impairing ATP production 1
Mitochondrial DNA damage results from direct interaction between anthracyclines and mitochondrial DNA, which lacks the protective histones found in nuclear DNA 1
Altered calcium handling develops when anthracycline-induced changes in mitochondrial membrane permeability disrupt intracellular calcium ion flux, ultimately affecting contractility 1
Enhanced ROS formation creates a vicious cycle—abnormal respiratory chain function generates additional ROS, which further damages the respiratory chain and mitochondrial DNA 1
Cellular Consequences
Myocyte morphological changes are characteristic of anthracycline cardiomyopathy: sarcoplasmic reticulum vacuolization, myofibril distortion and depletion, mitochondrial edema, and ultimately myocyte death 1
Progressive myocyte loss leads to initial diastolic dysfunction followed by systolic dysfunction and heart failure as the heart's functional reserve is exceeded 1
Nonischemic cellular degeneration distinguishes anthracycline cardiotoxicity from ischemic cardiomyopathy—the damage pattern is diffuse rather than regional 1