Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Abstract

The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

Induction of Apoptosis in Human Oral Keratinocyte by Doxorubicin

“…The present study demonstrated that doxorubicin induced apoptosis also in human normal oral keratinocytes, like that has previously been published in various cancer cells (11)(12)(13). This indicates the induction of apoptosis itself does not guarantee the anti-tumor potential.…”

“…This points out that keratinocyte toxicity is new adverse effect of anticancer agents, in addition to cardiomyopathy (11). Further study is required to elucidate why human oral keratinocytes are more sensitive to anticancer drugs compared to human mesenchymal cells.…”

Possible mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour

“…[6][7][8] Irrespective of the cause of death, the dying/ dead cells must be eliminated from the myocardium, a task usually performed by macrophages. Patient 1 suffered from heart failure due to doxorubicininduced cardiomyopathy.…”

“…With doxorubicin-induced cardiomyopathy, cardiomyocytes reportedly die via apoptosis or necrosis. [6][7][8] Irrespective of the cause of death, the dying/ dead cells must be eliminated from the myocardium, a task usually performed by macrophages. In general, however, macrophages are not frequently present within the myocardium in cases of doxorubicin-induced cardiomyopathy.…”

Markers of Heart, Lung and Dorsal Aorta Damage of Mother Rats and Their Neonates Post Therapeutic Treatment with Doxorubicin, Cisplatin and 5-Flurouracil

“…Both cardiac and lung diseases may be attributed to the increased oxidative stress, inflammation and DNA damage in the vascular cells [55] leading to apoptosis [56].…”