Date Published: June 29, 2017
Publisher: Public Library of Science
Author(s): Izabela Piotrowska, Mark Isalan, Michal Mielcarek, Germán E. González.
Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects. Hence, a number of studies have defined a “safe dose” of the drug, both in animal models and clinical settings, with the aim of avoiding long-term cardiac effects. Here we show that a dose generally considered as safe in a mouse model can induce harmful changes in the myocardium, as early as 2 weeks after infusion. The adverse changes include the development of fibrotic lesions, disarray of cardiomyocytes and a major transcription dysregulation. Importantly, low-dose doxorubicin caused specific changes in the transcriptional profile of several histone deacetylases (HDACs) which are epigenetic regulators of cardiac remodelling. This suggests that cardioprotective therapies, aimed at modulating HDACs during doxorubicin treatment, deserve further exploration.
Cardiac remodelling occurs in response to many pathological and toxic stimuli, including genetic abnormalities and chronic administration of cardiotoxic small molecules. Anthracyclines like doxorubicin (adriamycin) are widely used anticancer drugs and constitute part of the standard chemotherapeutical regime for a broad spectrum of malignancies, due to their high effectiveness . They cause, however, both acute and chronic dose-dependent cardiac injury, which severely restricts their use . Although acute doxorubicin-induced cardiotoxicity is mostly manageable in clinical settings, delayed, life-threatening, anthracycline-associated heart failure can appear even decades after cancer treatment. Over the last decades, a number of groups developed mouse models that mimic doxorubicin induced cardiomyopathy. It has been widely demonstrated that doxorubicin causes cell death of cardiomyocytes followed by the appearance of interstitial fibrosis that, on a physiological level, is manifested by a reduction of the ventricular ejection fraction and contractile function (for a review see [3,4]).
We tested the hypothesis that chronic infusion of a relatively low dose of doxorubicin can induce adverse cardiac remodelling in murine hearts. We administered doxorubicin to wild type (WT) female mice, from 10 weeks of age, for two weeks. Both groups (PBS vehicle and doxorubicin) had comparable body weights at both the start (Fig 1A) and at the end of the trial (Fig 1B). The groups also had comparable tibia lengths at 12 weeks of age (Fig 1C), indicating that there were no gross differences in growth. However, chronic treatment with doxorubicin led to a significant increase in heart weight (Fig 1D). Consequently, the HW/TL index (Heart Weight to Tibia Length) was significantly increased in the WT doxorubicin group, in comparison to the WT vehicle (PBS) group (Fig 1E). We did not observe any general adverse effects that are common in humans, such as eye or skin irritation, or hair loss. Local toxicity or vesicant effects of doxorubicin (tissue damage from escaping out of the vein) do not occur with Alzet pumps and so were also absent. Overall, we conclude from this morphometric analysis that doxorubicin treatment at low dose (15 μg/g infusion) was cardiotoxic and led to a cardiomyopathy that is similar to that previously described for a higher cumulative dose of doxorubicin (24 μg/g) .
Anthracyclines such as doxorubicin (adriamycin) are widely-used anticancer drugs, with a proven therapeutic potential in many haematological cancers and solid malignancies . Despite the beneficial effect of doxorubicin in cancer, it is well-established that this drug causes a severe cardiomyopathy, and heart failure is observed in doxorubicin-treated cancer patients . Although the precise mechanism of doxorubicin’s cardiotoxicity remains largely unknown, there have been a number of studies suggesting that doxorubicin might act through oxidative stress, including superoxide radical production, mitochondrial DNA damage, or even an imbalance in calcium or iron homeostasis; for a review see . However, until now, little has been known about whether doxorubicin changes epigenetic regulation in the heart. Hence, we sought to establish whether there were any changes in the transcriptional signature of histone deacetylases (Hdacs), using a well-established mouse model with chronic administration of doxorubicin [26,27].