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European Heart Journal Advance Access originally published online on April 19, 2006
European Heart Journal 2006 27(10):1251-1256; doi:10.1093/eurheartj/ehl003
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression

Tomas G. Neilan1,*, Davinder S. Jassal2, Michael F. Scully1, Gang Chen4, Catherine Deflandre6, Hester McAllister6, Elaine Kay5, Sandra C. Austin1, Elkan F. Halpern3, Judy H. Harmey4 and Desmond J. Fitzgerald1

1 Department of Clinical Pharmacology, Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
2 Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, USA
3 The Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA
4 Department of Surgery, Beaumont Hospital, Dublin, Ireland
5 Department of Pathology, Beaumont Hospital, Dublin, Ireland
6 Department of Veterinary Medicine, University College Dublin, Ireland

Received 21 July 2004; revised 15 March 2006; accepted 6 April 2006; online publish-ahead-of-print 19 April 2006.

* Corresponding author. Tel: +1 617 7241991; Fax: +001 617 7268383. E-mail address: tneilan{at}partners.org

See page 1137 for the editorial comment on this article (doi:10.1093/eurheartj/ehi702)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims The use of doxorubicin (DOX) as a chemotherapeutic agent is limited by cardiac injury. Iloprost, a stable synthetic analogue of prostacyclin, has previously been shown to protect against DOX-induced cardiomyocyte injury in vitro. Here, we addressed whether iloprost is cardioprotective in vivo and whether it compromises the anti-tumour efficacy of DOX.

Methods and results Lewis Lung Carcinoma cells were implanted subcutaneously in the flank of C57BL/6 mice. DOX treatment was commenced from when tumours became visible. Iloprost was administered from prior to DOX treatment until sacrifice. Echocardiography and invasive haemodynamic measurements were performed immediately before sacrifice. As expected, DOX induced cardiac cell apoptosis and cardiac dysfunction, both of which were attenuated by iloprost. Also, iloprost alone had no effect on tumor growth and indeed, did not alter the DOX-induced suppression of this growth.

Conclusion In a murine model, iloprost attenuated the acute cardiac injury and dysfunction induced by DOX therapy without compromising its chemotherapeutic effect.

Key Words: Doxorubicin • Cardiotoxicity • Cyclooxygenase • Prostaglandins


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Doxorubicin (DOX) (Adriamycin) is a broad spectrum chemotherapeutic agent used in the treatment of both haematological and solid tumours. However, clinical efficacy is complicated by a dose-related cardiotoxicity,1 so that the dose used is strictly limited. Even at these restricted doses, cardiac toxicity occurs. The relative risk of cardiac death is significantly greater than the normal population even up to 25 years after therapy with DOX for childhood malignancy.2 The cardiac injury induced by DOX takes many forms but the most clinically relevant is the development of dilated cardiomyopathy. This has been reported in up to 30% of patients when DOX is combined with Herceptin, an antibody to the HER-2 receptor used in the treatment of breast cancer.3 Also, the cardiomyopathy due to DOX therapy may manifest months to years after treatment.4 This long interval between treatment and diagnosis may limit screening methods.

A number of mechanisms may contribute to DOX-induced cardiomyocyte injury,1 but free-radical mediated damage has been suggested as the most likely.5 Free radicals generated from DOX target mitochondria predominantly, resulting in the induction of cardiomyocyte apoptosis.6 Recently, we demonstrated that DOX induces cyclooxygenase (COX)-2 through free-radical mediated activation of MAP kinases, including Erk1/2.7 The induction of COX-2 protected the cells from DOX-mediated toxicity, as inhibition of COX-2 increased the DOX-induced release of cardiac enzymes, whereas iloprost, a synthetic prostacyclin (PGI2) analogue, protected the cells. Similarly, in vivo, iloprost protected against the DOX-induced increase in cardiac apoptosis and troponin level in the rat.8 However, it is unclear whether this translates into preservation of cardiac function. Moreover, prostaglandins and COX also promote tumour growth;9 this may limit the usefulness of these products in this setting. We assessed whether DOX-induced cardiac dysfunction could be prevented by co-administration of a PGI2 analogue and whether administration of this analogue reduced the chemotherapeutic efficacy of DOX in a murine tumour-bearing model.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Materials
Iloprost was a kind gift from Schering AG, Berlin, Germany, whereas DOX HCL was purchased from Pharmacia, Milan, Italy. Lewis Lung Carcinoma cells were obtained from the American Tissue Culture Collection (ATCC, CRL-1642).

Experimental protocol
All animal experiments were performed under license from the Department of Health under the Cruelty to Animals Act of 1876. Animal care was conducted in conformity with institutional guidelines and in compliance with international laws and policies. All cancer experiments were performed in line with the UKCCCR guidelines for the Welfare of Animals in Experimental Neoplasia.10 Male C57BL/6 mice aged 10–12 weeks and weighing 25–30 g were randomly separated into four experimental groups and injected with (i) vehicle (n=8), (ii) the PGI2 analogue, iloprost (n=9), (iii) DOX (n=10), or (iv) DOX plus iloprost (n=10). DOX was administered intraperitoneally at a cumulative dose of 24 mg/kg in three equal doses over alternate days beginning when tumours were visible (Figure 1). Iloprost was also administered intraperitoneally at a dose of 12 µg/kg twice daily in Tris-buffered (0.05 mol/L, pH 8) isotonic saline and 10 mL/L 96% ethanol. Iloprost treatment was commenced 4 days prior to DOX chemotherapy and continued until sacrifice, 5 days following completion of the DOX. Control animals received equal volumes of vehicle. These doses and their timing were based on previous work done in this laboratory8 and pre-experimental dose–response curves (data not shown).


Figure 0031
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  		Figure 1 Effect of DOX alone and in combination with iloprost on tumour growth. On the basis of preliminary work, we predicted that tumours would be readily visible 10–12 days after inoculation. Iloprost (12 µg/kg bid) was initiated 4 days prior to tumour appearance and prior to initiation of therapy with DOX. The cumulative dose of 24 mg/kg of DOX was administered as three doses of 8 mg/kg on days 1, 3, and 5 (arrows) after tumour appearance. Tumour growth was recorded every second day. There was no difference in tumour growth between control animals and animals treated with iloprost alone. Tumour growth was suppressed by DOX and treatment with iloprost did not affect the anti-tumour activity of DOX. Animals were sacrificed 10 days after commencement of chemotherapy.

 
Cell culture
Lewis Lung Carcinoma cells cultured in Dulbecco's modified Eagle's medium, supplemented with 10% heat-inactivated foetal calf serum, 100 U/mL penicillin and 100 µg/mL streptomycin sulphate were maintained in a humidified atmosphere of 5% CO2 in air at 37°C. The tumour cell line was chosen for the compatibility of this cell line with the mouse strain. Tumour cells were harvested, washed three times using Ca+/Mg2-free phosphate-buffered saline (PBS) and resuspended in PBS at a final concentration of 5x106 cells/mL for injection. Only cell suspensions of >95% viability were used for injections.

Tumour model
Mice were anaesthetized with 1% isoflurane/98% oxygen/1% CO2. The right flank was shaved, cleaned with antiseptic and 100 µL (5x105 cells) injected into the area subcutaneously. Mean tumour volume (MTV) was determined every second day by the ellipsoid volume formula (lengthxwidthxheightx0.52). Tumour growth was compared between groups by calculating the percentage change in tumour growth from baseline to sacrifice (%{Delta} MTV).

Transthoracic echocardiography
Transthoracic two-dimensional echocardiography was performed under inhalation anaesthesia on the day of sacrifice. The mice were anaesthetized using a mixture of 1% isoflurane/98% oxygen/1% CO2. The chest was shaved and animals were placed in the left lateral position. Thermoregulation was achieved using an auto-regulated heating blanket. Two-dimensional images were obtained in the parasternal short-axis view at a level close to the papillary muscles using a linear-array probe (15L8, Acuson, Mountain View, CA, USA) connected to a numeric Sequoia 512 ultrasound device (Acuson). Parameters measured digitally on the M-mode tracings and averaged over three cardiac cycles, included left ventricular internal dimensions in systole (LVIDs) and diastole (LVIDd). LV fractional shortening (FS) was calculated as [(LVIDd–LVIDs)/LVIDd]x100.

Invasive haemodynamic measurements
Intracardiac and systemic arterial pressures were obtained by retrograde catheterization of the carotid artery. Animals were anaesthetized with a combination of fluanisone/fentanyl (Hyponorm, Janssen Pharmaceuticals, Beerse, Belgium) and midazolam (Roche Pharmaceuticals, Dublin, Ireland). A micro-tip pressure catheter (SPR-671, 1.4 Fr, Millar Instruments Inc., TX, USA) was inserted into the right carotid and advanced under pressure control into the left ventricle. After a period of stabilization, signals were recorded continuously using a pressure conductance system (ARIA, Millar Instruments Inc.) coupled with a Powerlab/4SP AD converter (AD Instruments, Oxfordshire, UK). The LV end-diastolic pressure (LVEDP) and end-systolic pressure (LVESP) and maximal and minimal rate of change of systolic and diastolic pressures, dP/dtMAX and dP/dtMIN, respectively, were measured. Subsequently, the catheter was withdrawn into the aorta for measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate.

Histological assessment of myocardial damage
The animals were sacrificed under anesthesia at the end of cardiac catheterization and the hearts removed into a formalin/saline mixture (0.9% NaCl, 10% formaldehyde) and fixed for 24 h. Cardiac tissue sections were chosen randomly from five animals in each group and were stained with Haematoxylin and Eosin (H&E) and Massons Trichrome for detection of fibrosis. An independent observer, blinded to study groups, performed the histological analysis.

In situ terminal deoxynucleotidyl transferase assay (TUNEL)
The terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick-end labelling technique (TUNEL) was performed with the Apoptag system according to manufacturers protocol (Serologicals Corporation, Norcross, CA, USA). DNA fragments, which had been labelled with a digoxigenin-dUTP nucleotide complex, were detected using peroxidase-conjugated anti-digoxigenin antibody. Quantitative analysis was performed using Image-Pro plus 4.1 software (Media Cybernetics, Silver Spring, MD, USA).

Statistical analysis
All data are expressed as mean±SEM. All tests were two-sided as appropriate. On the basis of preliminary data, we hypothesized that DOX would induce a decrease in the dP/dtMAX of ~50% within the time frame of the experiment. Therefore, allowing for a standard deviation of 1672, a power of 0.90 and a P-value of 0.05, we estimated that we would require at least eight surviving animals in each group. Again from preliminary data, we estimated that two to three mice would die within this time frame after DOX treatment, thus necessitating two more mice in the DOX-treated groups when compared with the control group. The cardiovascular effects of interest were only measured at sacrifice. For analysis of these effects, final comparisons among groups were made by analysis of variance using factors for the presence of DOX, iloprost, and the interaction of these two factors. For comparisons of serial measures of tumour growth within groups, repeated analysis of variance was used. If the repeated measures were significant a post hoc analysis was performed with the Dunnett's test as appropriate. We used fixed grouping effects for DOX, iloprost, and the interaction of these factors. We were specifically interested in the effects of DOX and the combination of DOX/iloprost on the FS and the dP/dtMAX 5 days after treatment and the effects of DOX, iloprost, and the interaction of DOX/iloprost on tumour growth over time. However, to account for type 1 error due to multiple testing, only probability values of <0.01 were considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Tumour growth
In control animals, tumour size increased 10-fold from initial appearance to the day of sacrifice (control group, 121±16 at baseline vs. 1188±144 mm3 at sacrifice). However, tumour size, as assessed by MTV and mean tumour diameter (data not shown), was unchanged in the DOX group (tumour volume at baseline in the DOX alone group 207±25 at baseline vs. 140±24 mm3 tumour volume at sacrifice, P=0.57), and this was unaltered by co-treatment with iloprost (tumour volume at baseline in the DOX/iloprost group 208±26 vs. 152±23 mm3 tumour volume at sacrifice, P=0.47) (Figure 1). Iloprost alone had no effect on tumour growth (%{Delta} MTV from baseline 978±147 iloprost alone vs. 982±164 controls, P=0.78).

Cardiac function
The administration of DOX caused a reduction in cardiac function as measured by both echocardiography and intracardiac pressure measurements (Figure 2, Table 1). There was an overall significant effect of DOX on LVIDs, FS, LVEDP, LVESP, dP/dtMAX, dP/dtMIN, SBP, DBP, and mean arterial pressure (MAP) (P=0.02 for dP/dtMIN, all others P<0.001) and an effect for the interaction of DOX and Iloprost on LVIDs, FS, LVEDP, LVESP, dP/dtMAX, dP/dtMIN, (P=0.006 dP/dtMIN, all others P<0.001). DOX-treated animals had an increase in both LV internal dimensions in systole and diastole with a fall in FS. The dP/dtMAX fell dramatically while there was also a reduction in dP/dtMIN indicating diastolic dysfunction. The decline in LV function was associated with a sharp fall in blood pressure and heart rate as well as an increase in LVEDP. Iloprost pre-treatment attenuated the deleterious effects of DOX on invasive and non-invasive indices of LV function with an improvement in both FS and dP/dtMAX. Iloprost alone had no effect on haemodynamic measurements or echocardiographic parameters compared with vehicle other than a small non-significant decrease in LVESP.


Figure 0032
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  		Figure 2 Effect of iloprost on DOX-induced cardiac dysfunction. Haemodynamic measurements and echocardiography were performed 5 days after the final DOX dose. There was an overall significant main effect of DOX on LVIDs, FS, LVEDP, and dP/dtMAX (P<0.001 for all) and also a significant main effect for the interaction of DOX and Iloprost on LVIDs, FS, LVEDP, and dP/dtMAX (P<0.001 for all). Treatment with DOX caused an increase in LVIDs (A) and LVEDP (C); this was associated with a significant reduction in FS (B) and dP/dtMAX (D). These adverse effects on invasive and non-invasive indices of LV function were attenuated by treatment with iloprost. Results are mean of eight to 10 experiments in each group. *P<0.001 for the effect of DOX; #P<0.001 for the interaction of the DOX and iloprost combination.

 

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  		Table 1 Haemodynamic and echocardiographic parameters

 
Histological analysis
Cardiac tissue stained with H&E showed no apparent histological differences between controls and iloprost alone treated animals. However, in DOX-treated animals, scattered dead cells with pyknotic and fragmented myocardial nuclei were observed. Cardiac sections from animals treated with iloprost and DOX showed none of the pathological changes seen in the DOX group and were indistinguishable from controls. There was no difference in fibrosis between groups (data not shown).

Apoptosis
Apoptosis within sections of cardiac tissue was negligible for both control and iloprost-treated animals. DOX treatment caused an increase in the percentage of apoptotic cells (0.12±0.016 DOX vs. 0.002±0.002 control, P<0.001) (Figure 3A). Iloprost in combination with DOX decreased the percentage of TUNEL-positive cells by 88% (0.12±0.016 DOX vs. 0.014±0.005 DOX/PGI2, P<0.001) (Figure 3A). Quantitative analysis also showed mildly decreased numbers of cardiomyocytes per high power field in the DOX group. The DOX-induced reduction in cardiomyocyte number was attenuated by iloprost (Figure 3B).


Figure 0033
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  		Figure 3 TUNEL assay for cardiomyocyte apoptosis. TdT-mediated dUTP nick-end labelling positive cells stain brown. Apoptosis was rarely seen in controls. DOX administration resulted in apoptosis, which was prevented by co-administration of iloprost. Iloprost and DOX/iloprost-treated animals were similar to controls. The percentage increase in apoptosis in response to DOX therapy (A) was associated with a decrease in cardiomyocyte numbers (B). A total of over 170 000 cardiomyocytes were analysed in the experiment (original magnification x400). *P<0.001 for the effect of DOX; #P<0.001 for the interaction of the DOX and iloprost combination.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Here, we demonstrate in a murine model that iloprost attenuated the acute cardiac injury induced by DOX administration. In addition to its effects on LV dimensions and FS, the synthetic prostacyclin analogue prevented the DOX-induced reduction in systolic function, measured as dP/dtMAX, and diastolic function, measured as dP/dtMIN. The findings are consistent with our earlier study that focused on the cardiac enzyme and cell death responses to DOX.8 Iloprost alone had little effect on LV dimensions or on contractile function, although it did reduce LVESP marginally, and acute administration was associated with a transient fall in MAP that returned to normal within 45 min (data not shown). Furthermore, iloprost reduced the histological evidence of injury and the apoptotic response to DOX, suggesting a direct cardioprotective effect. Despite the reduction in cardiac injury, iloprost did not reduce the anti-tumour efficacy of DOX.

The chemotherapeutic and the cardiotoxic effects of DOX may differ.11 The anti-tumour effects include inhibition of topoisomerase {Pi}12 and alteration of DNA binding and alkylation13 and are possibly independent of free radical formation.11 In contrast, there is strong evidence supporting a free-radical mediated mechanism for cardiomyocyte toxicity.14 There are several mechanisms by which radicals are formed from DOX. The quinine moiety of DOX may undergo redox activation in the presence of flavoprotein reductases (e.g. cytochrome P450 reductase, mitochondrial NADH dehydrogenase, and endothelial nitric oxide synthase) to a semi-quinone intermediate; this generates superoxide anions in the presence of molecular oxygen.15 An alternative mechanism is by formation of an iron complex, which participates in the generation of both superoxide and hydroxyl radicals.16 Hydroxamic acids, the only agent licensed for cardioprotection during DOX treatment, chelate iron and deplete intracellular iron stores to prevent the anthracycline–iron complex formation.17

DOX induces several pro-apoptotic genes including Fas6 and procaspase-3 and decreases the expression of Bcl-xL,18 an anti-apoptotic member of the Bcl family. DOX also induces other genes that protect the cell, including heat shock proteins.19 Among the potentially protective genes is COX-2, expression of which is induced by DOX in isolated rat neonatal cells and in the adult rat heart in vivo.7,8 COX-2 is also induced by hypoxia and by oxidant stress, the latter through activation of MAP kinases.20 Indeed, DOX-induced COX-2 expression is suppressed by antioxidants and by inhibition of Erk1/2.7

Increased expression of COX-2 has also been linked to almost every tumour type21 and COX-2 expression may be related to prognosis.9 Both chemical inhibition and genetic disruption of COX-2 are associated with a reduction in tumour growth.22 The COX-2 product and mechanism that mediates this increased tumour growth is unclear. The tumour-promoting activity of COX-2 is more likely to involve either PGE2 or thromboxane,23 rather than PGD2 and PGI2,23 supporting the lack of effect of iloprost seen in our model.

The predominant product of COX-2 in the heart is PGI2, the receptor for which (IP) is also highly expressed in murine cardiomyocytes.24 In the heart, COX-2 induction appears to protect against several forms of injury. For example, COX-2 is one of the genes responsible for pre-conditioning,25 the ability to recover from insult following a brief period of ischaemia. Moreover, PGI2, the principal COX product in the heart appears to be cardioprotective as disruption of the prostacyclin (IP) receptor aggravates cardiac ischaemia.26 Likewise, induction of COX-2 protects against the cardiotoxicity of DOX in rat neonatal cardiomyocytes and this appears to be mediated through increased PGI2 generation.7 The protective effect of COX-2 can be mimicked by the prostacyclin analogue, iloprost, both in vitro and in vivo, without promoting tumour growth, suggesting that this protection is through augmentation of this physiological COX-2 induction response. How iloprost protects the heart is unclear but may involve a nuclear hormone receptor, the peroxisome proliferator-activated receptors (PPARs). There are three isoforms PPAR{alpha}, {gamma}, and {delta}. PGI2 is a ligand for both PPAR{alpha} and for PPAR{delta}.27 Activation of PPAR{alpha} by synthetic ligands has been shown to be cardioprotective,28 whereas activation of PPAR{delta} has been shown to be antiapoptotic.29

This study has several limitations; it is an acute DOX-induced cardiac injury model in mice and may not accurately reflect the chronic cardiotoxicity seen in patients. The animals were monitored for a relatively short period after introduction of a tumour and a chronic effect by iloprost on tumour growth or a late reduction in cardiac function in iloprost-protected animals cannot be excluded. The tumours were exogenously introduced from a cancer cell line chosen for its synergism with this strain of mouse; however, we did confirm the expression of the IP receptor in this cell line prior to commencement of this study (data not shown). Iloprost is not selective for the IP receptor with partial agonist activity demonstrated at the PGE2 receptor. Thus, the protective effects of COX-2 may not be mediated via prostacyclin alone.

In conclusion, this study supports further research into the role for COX system of enzymes and prostaglandins in protection against DOX-induced cardiac injury. Expansion and definition of the mechanisms involved may ultimately define a clinical role for this pathway in providing cardiac protection for patients requiring chemotherapy.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
Supported by a grant from the Health Research Board and by the Higher Education Authority of Ireland Programme for Research in Third Level Institutions.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Y. Kuramochi, H. Takagi, and T. Morita
Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumor suppression
Eur. Heart J., November 1, 2006; 27(21): 2610 - 2611.
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P. G. Horan, M. F. McMullin, and P. P. McKeown
Anthracycline cardiotoxicity
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