The xanthine oxidase inhibitor oxypurinol reduces cancer cachexia-induced cardiomyopathy

https://doi.org/10.1016/j.ijcard.2013.05.063Get rights and content

Abstract

Background

Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure.

Methods

The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11.

Results

Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61 ± 4%) or 40 mg/kg/d (64 ± 5%) oxypurinol vs placebo (51 ± 3%, both p < 0.05). Fractional shortening was improved by 4 mg/kg/d (43 ± 3%) oxypurinol vs placebo (30 ± 2, p < 0.05), while 40 mg/kg/d oxypurinol (41 ± 5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71 ± 11 mL/min vs placebo 38 ± 4 mL/min, p < 0.01).

Conclusion

Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia.

Introduction

Depending on the type of cancer, cachexia is present in up to 80% of terminally-ill cancer patients [1]. Cachexia is characterized by progressive tissue wasting and weight loss, associated with a general hypercatabolism that results in reduced quality of life, impaired response towards anti-tumour therapy and ultimately a worse overall outcome. In fact, cancer cachexia is considered to be the cause of death in 22% of cancer patients [2]. However, the exact cause of death in cancer cachexia is unknown. Interestingly, hyperuricaemia is often observed in cancer patients, which seems to be independent from tumour lysis syndrome [3] and to be a negative prognostic marker in end-stage cancer patients [4].

Several lines of evidence, both clinical and experimental, have suggested that the inhibition of xanthine oxidase (XO) by allopurinol, oxypurinol or febuxostat has beneficial effects on cardiac function in heart failure [5], [6], [7]. The inclusion of uric acid assessment for risk stratification in heart failure patients has recently been suggested [8], as increased uric acid levels resulting form up-regulated XO activity have been shown to have predictive value for mortality in CHF [9]. However, lowering of uric acid serum levels alone without inhibiting XO did not have a positive effect on hemodynamic parameters in CHF patients [10]. Therefore, the inhibition of XO seems to be crucial in this context. This may be due to the production of large amounts of reactive oxygen species (ROS) as by-products during the metabolising of purine to uric acid by XO [11]. Recently, we showed increased uric acid levels and increased markers of oxidative stress in the Yoshida hepatoma cancer cachexia model, as well as an approximately 52-fold induction of XO-produced reactive oxygen species [12]. Inhibition of XO not only reduced uric acid levels and oxidative stress, but also wasting of body weight, muscle and fat mass, and significantly improved survival [12]. Interestingly, several groups have shown that experimental cancer cachexia does not only lead to skeletal muscle atrophy, but also to a strong reduction of cardiac mass [13], [14], [15]. This cardiac atrophy in cancer cachexia has been described to result in an impaired cardiac function [14]. The magnitude of these effects on the heart were also shown to be gender specific, with male mice being more affected [15].

Given the above described positive effects of XO-inhibition on cardiac function in CHF-patients with increased uric acid levels and the published data on a cardiomyopathy in experimental cancer cachexia, we hypothesised that the inhibition of XO by oxypurinol may reduce cardiac atrophy and have beneficial effects on cardiac function in the Yoshida AH-130 hepatoma cancer cachexia model.

Section snippets

Tumour model

Male Wister rats (mean weight 208 ± 1 g) were injected intra-peritoneally with 108 Yoshida AH 130 tumour cells as described previously [16] and randomized into the following groups: placebo (n = 22), 4 mg/kg/d oxypurinol (n = 12) or 40 mg/kg/d oxypurinol (n = 11). Additionally, three groups were injected with saline (= sham, n = 10, oxypurinol 4 or 40 mg/kg/d (both n = 4)) and used as a reference. The procedures were approved by the local animal ethics committee (G 0114/08, LaGeSo Berlin, Germany). Animals were

Results

As described before, inhibition of XO by oxypurinol significantly reduced mortality in this rat model of cancer cachexia [12]. In untreated rats uric acid was significantly increased in tumour-bearing rats compared to sham (Fig. 1). Treatment with oxypurinol reduced uric acid levels not only in tumour-bearing rats, but also in sham rats. However, no statistical significant difference was seen between the two doses of oxypurinol (Fig. 1). Also, the average loss of body weight was reduced by

Cardiac function

Baseline echocardiography showed no differences between groups (data not shown). On day 11 of the protocol, left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS) were reduced (by 32% and 43%, respectively) in placebo tumour bearing rats compared to sham and treatment with 4 or 40 mg/kg/d oxypurinol significantly increased both parameters in tumour-bearing rats (Fig. 3A and B). The LV end-diastolic diameter (LVEDD) was significantly lower in placebo tumour-bearing

Discussion

The main finding of this study is that pharmacological inhibition of XO by oxypurinol resulted in a reduced loss of body weight and improved cardiac function. Moreover, 4 mg/kg/d oxypurinol reduced wasting of cardiac mass in tumour-bearing rats, which was assessed by overall heart weight at the end of the study and by LV mass values calculated from echocardiographic images on day 11. Cardiac function was improved by both oxypurinol doses compared to placebo-treated tumour-bearing rats. However,

References (24)

  • J. Hammarsten et al.

    Clinical, haemodynamic, anthropometric, metabolic and insulin profile of men with high-stage and high-grade clinical prostate cancer

    Blood Press

    (2004)
  • S.D. Anker et al.

    Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging

    Circulation

    (2003)

    • Cited by (36)

    • Design, synthesis, biological evaluation of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehydes as non-purine xanthine oxidase inhibitors: Tracing the anticancer mechanism via xanthine oxidase inhibition

      2021, Bioorganic Chemistry
      Citation Excerpt :

      Thus, considering the importance of XOIs and problems associated with existing XOI, search for novel, more efficacious yet safer XOIs is further necessitated. Despite the strong association between XO along with its products and cancer, a few XOIs[34,35] have been studied for their development as anticancer agents for the treatment of the XO overexpressing tumor and interestingly none of the compound utilized as a chemical probe for understanding the mechanistic aspects in cancer cell lines. Cancer cells possess ROS approximately near to threshold and, low level of antioxidant enzymes, which make them more susceptible towards oxidative stress than normal cells [36].

    • Exercise Training as Therapy for Cancer-Induced Cardiac Cachexia

      2018, Trends in Molecular Medicine
      Citation Excerpt :

      Further data showing cardiac functional impairment stem from preclinical studies (Table 2). Two different models, the CD2F1 mouse model inoculated with C26 adenocarcinoma and the Wistar–Han rat model inoculated with Ah-130 hepatoma cells, consistently showed reduced left ventricular fractional shortening (LVFS) and LVEF compared with the respective model without cancer [19–25]. Accordingly, in vitro analysis performed in isolated cardiomyocytes from CD2F1 mice with colon-26 (C26) adenocarcinoma revealed impaired contractile function (time-to-90% shortening and time-to-90% relengthening increased) compared with isolated cardiomyocytes from control mice [26].

    • Uric acid and xanthine oxidase in heart failure - Emerging data and therapeutic implications

      2016, International Journal of Cardiology
      Citation Excerpt :

      Multiple pathophysiologic features of HF were shown to improve after XO inhibition such as myocardial mechanical [8,49] and energetic efficiency [9], left ventricular ejection fraction [10], cardiac remodeling [12], endothelium dysfunction [13], peripheral tissue perfusion [47], and plasma BNP levels [14]. Whether anti-cachectic effects that are seen in experimental studies [50–55] can be reproduced in clinically relevant settings, needs to be seen in clinical trials that are in part already ongoing [56,57]. Of current interest in this context is also whether nutrition interventions [58,59] or exercise [60–62] can be synergistic with anti-cachexia therapy.

    • Regulator of G-protein signaling 6 (RGS6) in cardiology and oncology

      2015, International Journal of Cardiology

    • Regulator of G-protein signaling 2 (RGS2) in cardiology and oncology

      2015, International Journal of Cardiology

    • Insights into cardio-oncology: The patient's heavy cancer journey among doubts, controversies and pitfalls. The role of the cardiologist

      2015, International Journal of Cardiology
    View all citing articles on Scopus
    1

    Equal contribution.

    View full text
    Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.