European Heart Journal Advance Access originally published online on October 3, 2006
European Heart Journal 2006 27(21):2610-2611; doi:10.1093/eurheartj/ehl293
Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumor suppression
Department of Pediatrics
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Department of Cardiovascular Surgery
Shizuoka Medical Center
Shizuoka 411-8611
Japan
Department of Pediatrics
Shizuoka Medical Center
Shizuoka 411-8611
Japan
The article by Neilan et al.1 [May 27(10) issue of this journal] is of interest to us. Their group has documented that iloprost attenuates the doxorubicin (DOX)-induced cardiac cell death in vitro and in vivo.2,3 They extend the work and estimate the effect of iloprost on DOX-induced cardiac dysfunction and anti-cancer therapy. Their message is clear, but this study raises some questions.
The authors mention that cardiac sections from animals treated with iloprost+DOX show none of the pathological changes seen in the DOX group and are indistinguishable from controls. Certainly, iloprost attenuates DOX-triggered cardiac cell death and dysfunction. However, there are around 4–5% of cardiomyocyte loss even in iloprost+DOX group with a small increase of TUNEL-positive cells (cf. about 10% of cell reduction in DOX group; Figure 31). Why did the authors fail to detect such a huge change in histological analysis? Moreover, the degradation of titin, a critical sarcomere player in the regulation of contractile function, is an early event in DOX-induced cardiac injury and consequent necrosis.4 In this animal model, comparatively high dose of DOX was used in short duration, and it might induce cardiomyocyte necrosis rather than apoptosis.5 Therefore, myofibrillar disarray may be a better parameter than cardiac fibrosis to estimate acute DOX toxicity.
Despite problems as mentioned earlier, their work is interesting since it has a potential that directly links to the strategy to prevent anthracycline cardiotoxicity. One of their next goals is the mechanism of this prostacycline protection against DOX-induced cardiac injury. Cicaprost, another prostacycline analogue, which activates IP and EP but not PPAR, may indicate a beneficial information. We are looking forward to their next challenge.
References
- Neilan TG, Jassal DS, Scully MF, Chen G, Deflandre C, McAllister H, Kay E, Austin SC, Halpern EF, Harmey JH. (2006) Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumor suppression. Eur Heart J 27:1251–1256.
[Abstract/Free Full Text] - Adderley SR and Fitzgerald DJ. (1999) Oxidative damage of cardiomyocytes is limited by extracellular regulated kinase 1/2-mediated induction of cyclooxygenase-2. J Biol Chem 274:5038–5046.
[Abstract/Free Full Text] - Dowd NP, Scully M, Adderley SR, Cunningham AJ, Fitzgerald DJ. (2001) Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury. in vivo. J Clin Invest 108:585–590.
- Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB. (2004) Anthracyclines induce calpain-dependnet titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279:8290–8299.
[Abstract/Free Full Text] - Sawyer DB, Fukazawa R, Arstall MA, Kelly RA. (1999) Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane. Circ Res 84:257–265.
[Abstract/Free Full Text]
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