Doxorubicin induced heart failure: Phenotype and molecular mechanisms

Abstract

Long term survival of childhood cancers is now more than 70%. Anthracyclines, including doxorubicin, are some of the most efficacious anticancer drugs available. However, its use as a chemotherapeutic agent is severely hindered by its dose-limiting toxicities. Most notably observed is cardiotoxicity, but other organ systems are also degraded by doxorubicin use. Despite the years of its use and the amount of information written about this drug, an understanding of its cellular mechanisms is not fully appreciated. The mechanisms by which doxorubicin induces cytotoxicity in target cancer cells have given insight about how the drug damages cardiomyocytes. The major mechanisms of doxorubicin actions are thought to be as an oxidant generator and as an inhibitor of topoisomerase 2. However, other signaling pathways are also invoked with significant consequences for the cardiomyocyte. Further the interaction between oxidant generation and topoisomerase function has only recently been appreciated and the consequences of this interaction are still not fully understood. The unfortunate consequences of doxorubicin within cardiomyocytes have promoted the search for new drugs and methods that can prevent or reverse the damage caused to the heart after treatment in cancer patients. Alternative protocols have lessened the impact on newly diagnosed cancer patients. However the years of doxorubicin use have generated a need for monitoring the onset of cardiotoxicity as well as understanding its potential long-term consequences. Although a fairly clear understanding of the short-term pathologic mechanisms of doxorubicin actions has been achieved, the long-term mechanisms of doxorubicin induced heart failure remain to be carefully delineated.

Doxorubicin‐induces NFAT/Fas/FasL cardiac apoptosis in rats through activation of calcineurin and P38 MAPK and inhibition of mTOR signalling pathways

“…In addition, the LVs of DOX‐treated rats demonstrated morphological and ultrastructural changes including sever cytoplasmic vacuolization, mitochondrial damage, and myofibrillar loss. All these changes have previously been described in similar animal models, as well as in the failing human heart, and were explained by multiple interconnected mechanisms including increased cell apoptosis, impaired Ca +2 homeostasis, down‐regulation of the contractile proteins synthesis, myocyte atrophy, and compensatory hypertrophy …”

“…In addition, the LVs of DOX-treated rats demonstrated morphological and ultrastructural changes including sever cytoplasmic vacuolization, mitochondrial damage, and myofibrillar loss. All these changes have previously been described in similar animal models, as well as in the failing human heart,3,32-34 and were explained by multiple interconnected mechanisms including increased cell apoptosis, impaired Ca +2 homeostasis, down-regulation of the contractile proteins synthesis, myocyte atrophy, and compensatory hypertrophy 8,33,[44][45][46]. On the other hand, numerous studies have shown that DOX administration activates both intrinsic and extrinsic cell death in severalF I G U R E 4 Doxorubicin (DOX) increases the activity of ERK, p-P38 MAPKs and inhibits mTOR activity in the left ventricle (LVs) of rats (A, C) and cultured cardiomyocytes (B, D) but enhances JNK activity in cultured cardiomyocytes (D).…”

“…Chronic exposure to doxorubicin (DOX), an antineoplastic drug, is associated with apoptosis in cardiac myocytes and the development of irreversible congestive heart failure (HF) . Although the precise molecular mechanisms remain unclear, accumulating evidence has indicated that the DOX‐induced apoptosis in cardiac myocytes owing to overproduction of reactive oxygen species (ROS), disturbance of Ca 2+ homeostasis, and mitochondrial damage, involving both intrinsic (mitochondria‐mediated) and the extrinsic [Fas/FasL (Fas ligand)‐mediated] pathways of cell death …”

Doxorubicin‐induced cardiotoxicity involves IFNγ‐mediated metabolic reprogramming in cardiomyocytes

“…The function and integrity of mature cardiomyocytes are mainly defined by their high energy requirements . In line with this, heart failure is linked to impaired mitochondrial function and disrupted lipid metabolism . Mitochondrial functioning in cardiomyocytes can be directly interrupted by reactive oxygen species derived from the reduction of DOX to 7‐deoxy‐doxorubicinone , intracellular iron accumulation, and loss of the iron balance .…”

Relationship between diastolic and systolic myocardial dysfunction at doxorubicin cardiomyopathy

“…Наи-более эффективным представителем этой группы являет-ся доксорубицин. Вызываемая им КМП характеризуется одинаковым симптомокомплексом у людей и животных [1,2], проявляющимся в виде систолической дисфункции (СД) левого желудочка (ЛЖ) и хронической сердечной недостаточности (ХСН) [3]. КМП, вызываемая ежене-дельным введением доксорубицина, развивается посте-пенно.…”