Role of carnitine in cancer chemotherapy-induced multiple organ toxicity

Abstract

In the last few years, cancer chemotherapy has been successfully employed in the treatment of different types of human tumours. Unfortunately, the optimal clinical usefulness of this important treatment modality is usually limited secondary to the development of life-threatening multiple organ toxicity. Cancer chemotherapy may cause these toxic effects by mechanisms not involved in their anticancer activity that can severely affect the life of patients and represent a direct cause of death. Several experimental and clinical studies have demonstrated that some important anticancer drugs interfere with the absorption, synthesis, and excretion of carnitine in non-tumour tissues, resulting in a secondary carnitine deficiency which is reversed by carnitine treatment without affecting anticancer therapeutic efficacy. Prototypes of anticancer drugs that alter carnitine system are doxorubicin, cisplatin, carboplatin, oxaliplatin, cyclophosphamide and ifosfamide. Furthermore, cachectic cancer patients are especially at risk for carnitine deficiency due to decreased oral intake and/or increased renal losses. Altered serum and urine carnitine levels have been reported in cancer patients with various forms of malignant diseases. Recent studies in our laboratory have demonstrated that carnitine deficiency constitute a risk factor and should be viewed as a mechanism during development of oxazaphosphorines-induced cardiotoxicity in rats. Similarly, inhibition of gene expression of heart fatty acid-binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model has been reported. In view of these facts and in view of irreplaceability of these important anticancer drugs, this review aimed to highlight the role of carnitine depletion and supplementation during development of chemotherapy-induced multiple organ toxicity.

Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline‐deprived myocardium: the effects of carnitine

“…Moreover, MMP‐2 has been shown to be upregulated in rat models of choline deficiency‐mediated liver cirrhosis and a similar pattern of expression has been observed for TIMP‐1 , TIMP‐2 and MMP‐9 . On the contrary, the impact of inadequate levels of carnitine on MMPs modulation has been found to result in suppressed ECM degradation . Except for their effect on the regulation of ECM homeostasis, MMPs interfere with cell survival, differentiation, inflammation and angiogenesis triggering the expression of vascular endothelial growth factor (VEGF) .…”

“…[54,57,58], TIMP-2 [54] and MMP-9 [57]. On the contrary, the impact of inadequate levels of carnitine on MMPs modulation has been found to result in suppressed ECM degradation [59,60]. Except for their effect on the regulation of ECM homeostasis, MMPs interfere with cell survival, differentiation, inflammation and angiogenesis triggering the expression of vascular endothelial growth factor (VEGF) [61,62].…”

Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre‐puberty

“…Indeed, the search for protocols that reduce the reproductive side-effects of chemotherapy has been the main goal of studies using experimental models (Lirdi et al, 2008;Okada et al, 2009;Vendramini et al, 2010;Chao et al, 2011). Carnitine, an important quaternary amine (3-hydroxy-4-N,N,N-trimethylaminobutyrate), is an essential nutrient with a major role in cellular energy production and has been considered a promising cytoprotective agent (Sayed-Ahmed, 2010). It is acquired through exogenous dietary sources, mainly from meat and milk, and its endogenous production occurs in liver by the methylation of lysine and methionine requiring the presence of iron and three vitamins: ascorbic acid, niacin, and vitamin B6 (Cerretelli & Marconi, 1990;Evans & Fornas, 2003;Ng et al, 2004).…”

Cytotoxicity and Oral Acute Toxicity Studies of b-mangostin Isolated from Cratoxylum arborescens

“…As increased creatinine level in serum is characterized in association to renal damage, this indicator is used to identify renal toxicity during drug administration. [29,30] Thus, the results recorded in this study suggest that β-mangostin did not affect the renal function.…”