Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system

Abstract

An efficient regulation of fuel metabolism in response to internal and environmental stimuli is a vital task that requires an intact carnitine system. The carnitine system, comprehensive of carnitine, its derivatives, and proteins involved in its transformation and transport, is indispensable for glucose and lipid metabolism in cells. Two major functions have been identified for the carnitine system: (1) to facilitate entry of long-chain fatty acids into mitochondria for their utilization in energy-generating processes; (2) to facilitate removal from mitochondria of short-chain and medium-chain fatty acids that accumulate as a result of normal and abnormal metabolism. In cancer patients, abnormalities of tumor tissue as well as nontumor tissue metabolism have been observed. Such abnormalities are supposed to contribute to deterioration of clinical status of patients, or might induce cancerogenesis by themselves. The carnitine system appears abnormally expressed both in tumor tissue, in such a way as to greatly reduce fatty acid beta-oxidation, and in nontumor tissue. In this view, the study of the carnitine system represents a tool to understand the molecular basis underlying the metabolism in normal and cancer cells. Some important anticancer drugs contribute to dysfunction of the carnitine system in nontumor tissues, which is reversed by carnitine treatment, without affecting anticancer therapeutic efficacy. In conclusion, a more complex approach to mechanisms that underlie tumor growth, which takes into account the altered metabolic pathways in cancer disease, could represent a challenge for the future of cancer research.

Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients

“…In mammalian cells, the carnitine system is essential for glucose and lipid turnover and it plays a crucial role in maintaining the energy metabolism (Breitkreutz et al, 2000;Peluso et al, 2000). Chemotherapy causes dysfunction of enzymes involved in the transport and trafficking of carnitines (Peluso et al, 2000) and, in addition, ifosfamide and cisplatin induce increased urinary excretion of these molecules (Dodson et al, 1989;Marthaler et al, 1999;Heuberger et al, 1998).…”

“…Chemotherapy causes dysfunction of enzymes involved in the transport and trafficking of carnitines (Peluso et al, 2000) and, in addition, ifosfamide and cisplatin induce increased urinary excretion of these molecules (Dodson et al, 1989;Marthaler et al, 1999;Heuberger et al, 1998). These effects may worsen the dysmetabolic syndrome associated with cancer (Tisdale, 1997) and increase side-effects of chemotherapy, like fatigue (Tisdale, 1997;Portenoy and Itri, 1999).…”

“…In light of recent biochemical investigations, it is possible that carnitine deficiency may have a role in the development of chemotherapy-induced fatigue (Dodson et al, 1989;Breitkreutz et al, 2000;Peluso et al, 2000). In humans, carnitine derives from food intake or biosynthesis from the metabolism of lysine and methionine.…”

“…In mammalian cells, carnitine and its products play a central role in the energy metabolism. Carnitine is indispensable for glucose and lipid turnover, and it is essential for mitochondrial fatty acid oxidation, which is the primary fuel source in heart and skeletal muscle (Peluso et al, 2000). Chemotherapy causes dysfunction of the carnitine system, which may contribute to a condition of asthenia due to the impaired energy metabolism (Breitkreutz et al, 2000;Peluso et al, 2000).…”

“…Carnitine is indispensable for glucose and lipid turnover, and it is essential for mitochondrial fatty acid oxidation, which is the primary fuel source in heart and skeletal muscle (Peluso et al, 2000). Chemotherapy causes dysfunction of the carnitine system, which may contribute to a condition of asthenia due to the impaired energy metabolism (Breitkreutz et al, 2000;Peluso et al, 2000). Ifosfamide and cisplatin alter major enzymatic pathways and they cause carnitine secondary deficiency after increasing urinary excretion of the molecule (Dodson et al, 1989;Heuberger et al, 1998;Marthaler et al, 1999).…”