Therapeutic strategies against cancer cachexia

Abstract

Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important and crucial aspect to be taken into consideration in the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible this triple approach in the course of the disease, even before the weight loss can be detected.

Upregulation of ZIP14 and Altered Zinc Homeostasis in Muscles in Pancreatic Cancer Cachexia

“…Cachexia is a debilitating muscle wasting disorder observed in over 85% of PDAC patients, and is a major contributor to poor quality of life, reduced tolerance to anti-neoplastic therapies, and decreased survival [12,13,48]. Cachectic patients exhibit a significant loss of skeletal and cardiac muscle mass, a function that contributes to their accelerated death from cardiac and respiratory muscle wasting [16,18]; however, there are currently no approved treatments for cachexia. Based on our previous studies identifying a crucial role for the metal ion transporter, ZIP14, in cachexia associated with colon, breast, and lung cancers, we examined the importance of the Zip14-zinc axis in PDAC-associated cachexia.…”

“…Cancer cachexia is characterized by a decrease in both energy intake and muscle protein synthesis, coupled with an increase in both energy expenditure and muscle protein degradation [13][14][15]. During cachexia development, loss of skeletal and cardiac muscle mass and/or function is often accompanied by anorexia, chronic inflammation, and adipose tissue lipolysis [5,13,14,16]. In particular, the wasting of cardiac and skeletal muscles compromises vital physiological functions, such as circulation (heart muscles), respiration (diaphragm muscles), and locomotion (limb muscles), and thereby contributes to a poor quality of life and reduced survival for PDAC patients [12,[16][17][18].…”

“…During cachexia development, loss of skeletal and cardiac muscle mass and/or function is often accompanied by anorexia, chronic inflammation, and adipose tissue lipolysis [5,13,14,16]. In particular, the wasting of cardiac and skeletal muscles compromises vital physiological functions, such as circulation (heart muscles), respiration (diaphragm muscles), and locomotion (limb muscles), and thereby contributes to a poor quality of life and reduced survival for PDAC patients [12,[16][17][18]. Furthermore, cachexia cannot be reversed by nutritional supplementation alone; this points to a systemic metabolic dysfunction in patients with this condition [5,14,18].…”

Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia

“…Several therapeutic interventions with multiple agents have been described and tested . Supplementation with omega‐3 fatty acids that reduce IL‐1 and TNF‐α production and improve the efficacy of nutritional support has been tested .…”

Aberrant Zip14 expression in muscle is associated with cachexia in a Bard1‐deficient mouse model of breast cancer metastasis

“…Cachexia is a debilitating syndrome characterized by a progressive loss of muscle mass and function. 1 Cachectic cancer patients also exhibit systemic metabolic dysfunction, adipose tissue wasting, and chronic inflammation. [2][3][4] Moreover, the reduced synthesis and increased degradation of muscle proteins coupled with a systemic increase in energy expenditure lead to the wasting of both cardiac and skeletal muscles in cancer patients.…”