Doxorubicin cardiomyopathy

Abstract

Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered.

Fig. 1

a Normal myocyte structure and without abnormal interstitial fibrosis. b Myofibrillar loss and vacuolization (Adria cells) and extensive diffuse fibrosis. (Published with permission from Takemura et al. [3])

Fig. 2

a Normal myocardium with little or no extracellular matrix changes and intact myocytes. b Same features in higher magnification. c Myocyte loss, matrix disorganization and diffuse fibrosis. (Published with permission from Takemura et al. [3])

Fig. 3

a Results of trypan blue exclusion assay in a typical experiment demonstrating that co-treatment with vincristine (VCR) markedly decreases doxorubicin (DOX)-induced cardiomyocyte death. b Results of a live/dead assay. With doxorubicin treatment alone for 24 h there was an increased proportion of dead cells (ethidium positive, EthD/red fluorescence) and a decreased proportion of live cells (calcein ester positive/green fluorescence) compared to vehicle treatment. With co-treatment with vincristine there were more live than dead cells. (Published with permission from Chatterjee et al. [58])

Fig. 4

The effects of increasing concentrations of vincristine (VCR) on the survival of cultured adult mouse myocytes exposed to doxorubicin (DOX; trypan blue assay). With doxorubicin treatment alone, myocyte survival was on average 50%. With vincristine co-treatment, survival was >85%. n = 5; ∗ p < 0.05. (Published with permission from Chatterjee et al. [58])

Fig. 5

The effects of pharmacologic inhibitors of PI3-K/AKT (LY294002, LY) and MEK/ERK (PD 98059, PD) on cell survival (trypan blue assay) with or without doxorubicin (DOX) and vincristine (VCR) co-treatment. Doxorubicin treatment alone was associated with decreased myocyte survival. The addition of the inhibitors further decreased survival of the cardiomyocytes. With vincristine co-treatment without the inhibitors, survival was >85%. With the addition of the inhibitors, protection by vincristine was significantly attenuated, suggesting that survival pathways are involved in the protective effect of vincristine. n = 5–6; ∗ p < 0.05. Con. = Control; Veh. = vehicle. (Published with permission from Chatterjee et al. [58])