The Janus‐Faced Role of Antioxidants in Cancer Cachexia: New Insights on the Established Concepts

Abstract

Chronic inflammation and excessive loss of skeletal muscle usually occur during cancer cachexia, leading to functional impairment and delaying the cure of cancer. The release of cytokines by tumor promotes the formation of reactive oxygen species (ROS), which in turn regulate catabolic pathways involved in muscle atrophy. ROS also exert a dual role within tumor itself, as they can either promote proliferation and vascularization or induce senescence and apoptosis. Accordingly, previous studies that used antioxidants to modulate these ROS-dependent mechanisms, in cancer and cancer cachexia, have obtained contradictory results, hence the need to gather the main findings of these studies and draw global conclusions in order to stimulate more oriented research in this field. Based on the literature reviewed in this paper, it appears that antioxidant supplementation is (1) beneficial in cancer cachectic patients with antioxidant deficiencies, (2) most likely harmful in cancer patients with adequate antioxidant status (i.e., lung, gastrointestinal, head and neck, and esophageal), and (3) not recommended when undergoing radiotherapy. At the moment, measuring the blood levels of antioxidants may help to identify patients with systemic deficiencies. This approach is simple to realize but could not be a gold standard method for cachexia, as it does not necessarily reflect the redox state in other organs, like muscle.

L‐Arginine Enhances Protein Synthesis by Phosphorylating mTOR (Thr 2446) in a Nitric Oxide‐Dependent Manner in C2C12 Cells

“…iNOS has been proven to be an important mediator in TNF α -induced cachectic muscle loss and in age-related muscle wasting (sarcopenia) [ 21 ]. Under pathological conditions, the activation of iNOS promotes muscle atrophy [ 62 ]. NO may exert both protective and pathological effects during muscle wasting, depending on quantitative effects as well as on the spatial arrangement of NOS [ 22 ].…”

Group I Paks support muscle regeneration and counteract cancer‐associated muscle atrophy

“…Cachexia appears in nearly 50% of patients with advanced stage of cancer and leads to progressive functional impairment, decreased quality of life with respiratory complications, and death can occur following the loss of 75% of skeletal muscle mass. [4][5][6] We have recently found that three genes encoding for proteins of the C-X-C motif chemokine receptor 4 pathway are down-regulated in the atrophying gastrocnemius of Yoshida hepatoma-bearing rats: stromal cell-derived factor 1, adenylate cyclase 7, and p21 protein-activated kinase 1 (Pak1). 7,8 Paks are Ser/Thr kinases acting as downstream effectors of the p21 small GTPases Rac1 and Cdc42.…”

(+)-Catechin in a 1:2 Complex with Lysine Inhibits Cancer Cell Migration and Metastatic Take in Mice

“…General antioxidants have been the subject of intense research for cancer prevention and treatment. Because these molecules indistinctively target different cell types (including tumor-resident non-malignant host cells, some of which promote and some of which repress tumor progression), because they are not selective for a given ROS produced at a precise subcellular location and because they can interfere with anticancer therapy, general antioxidants have unpredictable effects on cancer progression ( Bonner and Arbiser, 2014 ; Milkovic et al, 2014 ; Ozben, 2015 ; Assi and Rebillard, 2016 ; Russo et al, 2017 ). For examples, chronic vitamin E supplementation was found to significantly increase prostate cancer incidence in humans ( Klein et al, 2011 ), vitamin C has no significant anticancer effects even when administered intravenously at high dose ( Jacobs et al, 2015 ), and N -acetylcysteine can promote metastasis by improving the resistance of cancer cells to oxidative stress during cell detachment and in the blood stream ( Le Gal et al, 2015 ).…”