The xanthine oxidase inhibitor oxypurinol reduces cancer cachexia-induced cardiomyopathy
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,
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2018, Trends in Molecular MedicineCitation 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].
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2016, International Journal of CardiologyCitation 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.
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