Various factors produced by both host and tumor are thought to contribute to the development and progression of cancer cachexia ^[1][10]. These multiple factors ultimately disrupt the balance between protein synthesis and protein degradation, leading to a loss of muscle mass ^[2][3][11,12]. Dysfunction of the membrane stabilizing dystrophin-glycoprotein complex (DGC), characterized by reduced dystrophin expression and increased glycosylation of DGC proteins, has been shown in a mouse model of gastrointestinal cancer, indicating that a loss of communication between the muscle cell membrane and the extracellular matrix could be associated with cachexia ^[4][13]. Increased metabolic stress, which occurs as a consequence of tumor burden, nutritional deficiency and various medical interventions such as chemotherapy, contributes to the development of cancer cachexia by elevating REE and exacerbating muscle loss ^[5][9]. Anti-cancer interventions such as chemotherapy can cause discomfort, nausea and anorexia in some patients, leading to reduced food intake, metabolic changes and muscle loss ^[6][14]. Since oxidative stress is a major contributor to the development of cancer cachexia, factors able to mitigate excessive oxidative stress could have therapeutic potential.

Epigallocatechin-3-gallate (EGCG) is the dominant antioxidant in green and black tea extract, having antioxidant, anti-inflammatory and anti-cancer functions ^[9][34]. EGCG suppresses cancer cell proliferation, inducing cell apoptosis and inhibiting cell invasion and migration to attenuate tumor progression ^[10][52]. In cell culture, 48 h EGCG treatment suppressed the growth of Lewis lung carcinoma (LLC) cancer cells in a dose-dependent manner, confirming its anti-tumor effects ^[9][34]. In the LLC tumor-bearing mouse, 12 days of EGCG treatment reduced tumor mass and volume and attenuated the loss of body weight without altering anorexia ^[9][34]. The attenuation of muscle wasting was attributed to inhibition of NF-κB and the downstream E3 ligases, MuRF1 and atrogin-1. Furthermore, ECGC treatment decreased leukocytic infiltration, thus reducing inflammation in skeletal muscles of tumor-bearing mice ^[9][34]. In addition to the suppression of tumor growth, high dose EGCG treatment reduced the survival rate of a healthy, baby hamster kidney cells (BHK-21) by 50%, ^[9][34], suggesting that higher concentrations of EGCG cause cytotoxicity in normal cells and interrupt healthy cell growth. Given that EGCG treatment in the LLC-injected mice was administrated several days prior to tumor palpability, it remains to be determined whether the protective effect of EGCG on muscle mass was due to its anti-cancer effects or direct effects on the muscle. Moreover, EGCG has a low systemic bioavailability ^[11][53], which may reduce the efficacy of EGCG treatment in clinical studies and in vivo animal studies. EGCG treatment for cancer cachexia is a relatively preliminary concept in the field and further investigation is needed to confirm therapeutic potential.

Resveratrol is found most abundantly in the skin of grapes, peanuts and pine bark, and has been shown to exert anti-cancer effects in vitro and in vivo ^[12][54]. In Yoshida ascites hepatoma (AH-130) cells in vitro and in rats implanted with AH-130 cells, resveratrol administration reduced tumor cell number via induction of AH-130 cell apoptosis ^[12][54]. In Ehrlich ascitic carcinoma bearing mice, the combined treatment of resveratrol (10 mg/kg) with the chemotherapeutic drug, doxorubicin (5 mg/kg), twice a week via intraperitoneal injection, exerted the best reduction in tumor size and prolonged survival compared with either treatment alone ^[13][55]. These findings demonstrate the potential for resveratrol to enhance the anti-cancer effect of chemotherapies by decreasing inflammation and the oxidative stress associated with chemotherapy ^[13][55].

In mice injected with LP07 adenocarcinoma cells, the anti-cachectic effects of resveratrol (20 mg/kg/day for 15 days via intraperitoneal injection) were linked to activation of sirtuin-1 and attenuation of FoxO3 signaling ^[16][58]. Sirtuin-1 is a histone deacetylase enzyme that helps maintain muscle mitochondrial content and function ^[27][67]. The resveratrol-dependent activation of sirtuin-1 is proposed to improve mitochondrial biogenesis to alleviate oxidative stress in cachectic LP07 tumor-bearing mice ^[16][58]. FoxO3 is involved in the skeletal muscle ubiquitin-proteasome, autophagy-lysosomal and mitochondrial autophagy pathways ^[28][68]. However, resveratrol treatment also inhibited tumor growth, making it difficult to discern whether the attenuation of muscle wasting was due solely to a reduced tumor burden ^[16][58]. While these studies have shown promising effects of resveratrol, findings from other studies question the benefit of resveratrol for treating cancer cachexia. Intraperitoneal injection of resveratrol failed to attenuate the loss of muscle mass and body mass in LLC-tumor bearing mice (at both 5 mg/kg/day and 25 mg/kg/day for 15 days) and exacerbated the reduction in food intake and loss of gastrocnemius, heart and white adipose tissue mass in AH-130-tumor bearing rats (1 mg/kg/day for seven days) ^[15][57]. The discrepancies in the findings between the studies may be attributed to differences in animal models and/or tumor type ^[14][15][56,57]. Further studies are required to resolve these conflicts and determine the mechanisms underlying the therapeutic potential of resveratrol for cancer cachexia.

Curcumin, a component of turmeric, has been investigated as a potential treatment for cancer cachexia ^[29][69] due to its anti-inflammatory, antioxidative and anticarcinogenic functions as a nutritional supplement ^[17][18][28,59]. Curcumin is a nontoxic phytochemical with demonstrated potential to attenuate tumor growth in preclinical and clinical studies via suppression of NF-κB activity ^[18][30][59,70]. In MAC16 tumor-bearing mice, curcumin prevented muscle wasting and reversed existing muscle loss ^[17][28]. Treatment with curcumin c3 complex has been used in human clinical trials ^[31][71], where it protected skeletal muscle from wasting when orally administered a low dose (100 mg/kg/day) for 20 days, and induced weight gain relative to the control tumor-bearing group when administered at a higher dose (250 mg/kg/day) ^[17][28]. In MAC16 colon tumor-bearing mice, curcumin treatment attenuated the PIF-induced increase of the 20S proteasome, and decreased expression of NF-κB, atrogin-1 and MuRF1, indicating that protection from muscle wasting was attributed to suppression of the ubiquitin-proteasome pathway and subsequent protein degradation ^[17][28]. It should be noted that MAC16 colon tumor-bearing mice exhibit a gradual loss of body mass and muscle mass over 21 days, enabling the efficacy of curcumin supplementation to protect skeletal muscle mass to be assessed over a longer period ^[17][28]. Curcumin was also shown to attenuate loss of body mass and improve muscle mass and limb strength gain in cachectic LP07 tumor-bearing mice without altering tumor size ^[16][58]. These effects were associated with increased cross-sectional area (CSA) of type I and type II muscle fibers, and a reduced proportion of muscle fibers with internal nuclei and inflammatory cell infiltration, in gastrocnemius and soleus muscles ^[16][58]. Compared to studies reporting beneficial outcomes of curcumin, administration (20 µg/kg/day for six days via intraperitoneal injection) failed to improve the cachectic pathology in AH-130 tumor-bearing rats despite having anti-tumor effects ^[18][59]. The disparity in these reports may arise from differences in dose, route of administration and treatment duration in different animal models, as well as the low systemic bioavailability of curcumin ^[32][72].

While studies investigating curcumin efficacy in cancer cachexia did not measure oxidative stress directly, the role of curcumin for attenuating oxidative stress in skeletal muscle is well established. Curcumin reduced exercise-induced oxidative stress, evidenced by decreased levels of serum lactate and muscle MDA ^[33][73]. Oral curcumin treatment (100 mg/kg/day) for 14 days reduced hypobaric hypoxia-induced oxidative stress and increased muscle fiber number in Sprague Dawley rats ^[34][74]. The antioxidative effect of curcumin was linked with reduced activity of NF-κB and activation of Nrf2 signaling ^[33][73], effects that reflect regulation of redox balancing, protein synthesis and protein degradation. Thus, regulating redox balance may be one mechanism by which curcumin attenuates cancer cachexia.

The therapeutic potential of curcumin has also been explored in clinical trials. Based on the limited data available, curcumin reduced expression of NF-κB in some patients with pancreatic cancer ^[30][70]. Due to its poor oral absorption and weak bioavailability, curcumin supplementation had only limited benefit for these pancreatic cancer patients ^[30][70]. However, the difficulty in accurately determining redox status in skeletal muscle ^[35][75], may explain why evaluating the efficacy of antioxidant supplements like curcumin has proved challenging, especially when assessments in trials rely on measures of antioxidant levels in the blood. Improvements in the accuracy of these outcome measures are required to better evaluate the therapeutic potential of curcumin for cancer cachexia.

Carnosol is a bioactive diterpene compound present in rosemary, with antioxidant, anti-inflammatory and anti-cancer properties ^[19][60]. The antioxidative function of carnosol has been well characterized and includes protection from lipid peroxidation ^[36][76], suppression of nitric oxide production and gene expression of inducible nitric oxide synthase ^[37][77] and amelioration of the damage caused by UVB-induced ROS ^[38][78]. Carnosol can inhibit the activities of NF-κB signaling to protect against free radical damage ^[37][77] and it has been shown to reduce tumor growth in mouse models of intestinal cancer ^[39][79], breast cancer ^[40][80] and skin cancer ^[38][78].

Carnosol can protect against cancer-induced muscle wasting in in vitro and in vivo models ^[19][60]. Carnosol supplementation attenuated C2C12 myotube atrophy after exposure to C-26 cell conditioned media and ameliorated the loss of body mass in C-26 tumor-bearing mice ^[19][60]. These effects were associated with downregulation of MuRF1 expression and upregulation of Akt phosphorylation and MyoD expression, indicating suppressed protein degradation and increased protein synthesis ^[19][60]. Both in vitro and in vivo models showed reduced phosphorylation of p65, implicating a role for carnosol in suppressing NF-κB signaling in cancer cachexia ^[19][60]. While carnosol had a protective role in C-26 tumor-bearing mice by maintaining body mass and adipose tissue mass, skeletal muscle mass was not improved. This suggested the increase in body mass resulted from an attenuation of fat lipolysis rather than direct effects on the regulation of skeletal muscle mass ^[19][60]. These interesting findings warrant further investigation of the therapeutic potential of carnosol for cancer cachexia. Moreover, a recent study revealed the synergistic effect of carnosol and a chemotherapeutic drug, cisplatin, where combined therapy induced the highest rates of apoptosis in MCF-7 and MDA-MB-231 breast cancer cell lines ^[41][81]. Therefore, carnosol has potential to become part of a combination therapy in the treatment of cancer and cancer-induced muscle wasting.

Quercetin is an abundant flavonoid and prominent dietary antioxidant in various fruits and vegetables, such as onions, tomatoes and apples ^[42][82]. Quercetin has antioxidative and anti-inflammatory functions, and hence therapeutic potential for treating cancer ^[43][44][83,84]. Supplementation with quercetin (0.05% (w/w) in food) for nine weeks protected against TNF-α-induced skeletal muscle atrophy via activation of Nrf-2 signaling and inactivation of the NF-κB signaling pathway to overcome oxidative stress in the C57BL/6 mouse model of high fat diet-induced obesity, confirming the antioxidant and anti-inflammatory properties of quercetin ^[42][82]. Quercetin has significant bioavailability compared with other polyphenols, with detection in plasma 12 h after oral intake ^[21][62]. The high absorption in plasma was associated with whole body accumulation of quercetin since it was detected in different tissues such as the liver, skeletal muscle, heart and brain, resulting in the slow clearance of quercetin metabolites from the body ^[21][62].

Quercetin has been shown to protect against cancer-induced muscle wasting in vivo ^[20][21][61,62]. Oral administration of quercetin (25 mg/kg/day) to Apc^Min/+ mice for three weeks attenuated the loss of whole body mass and increased gastrocnemius and quadriceps muscle mass ^[20][61]. These effects may have resulted from reduced inflammation, based on the decrease in plasma IL-6 levels ^[20][61]. However, treatment failed to improve muscle function in the Apc^Min/+ mouse model of cancer cachexia ^[20][61]. Supplementation of 250 mg/kg quercetin to a daily chow diet for 20 days attenuated both the loss of body mass and the reduction in gastrocnemius and tibialis anterior muscle mass in C-26 tumor bearing mice, but did not improve grip strength ^[21][62]. Micro-CT analysis of the hindlimb revealed that quercetin supplementation completely prevented the tumor-induced reduction in muscle volume ^[21][62]. A substantial (albeit a non-statistically significant) decrease was detected in the expression of E3 ubiquitin ligases, atrogin-1 and MuRF1, in treated mice, indicating an attenuation of protein degradation. While these studies suggest a positive outcome of quercetin with a potential anti-cachectic function, the underlying mechanism remains undetermined. Interestingly, tumor mass was not significantly decreased with quercetin. Furthermore, the experiment did not control for the increase in food intake in the quercetin supplemented group ^[21][62]. While quercetin has proposed anti-cachectic benefits, a mechanism for these effects has not been established at the cellular level, and this diminishes the significance of these outcomes. Moreover, oral quercetin (50 mg/kg/day) for 1 h prior and during 15-day doxorubicin exposure, reduced chemotherapy-induced oxidative stress in the spleen via suppression of apoptosis, reducing inflammation and increasing the antioxidant response in Sprague–Dawley rats ^[45][85]. The protective effect of quercetin against chemotherapy-induced cytotoxicity indicates its potential for attenuating chemotherapy associated muscle atrophy in cancer cachexia. Future studies using pair-fed groups to control for potential treatment-related changes in food intake, as well as additional clinically relevant end-point analyses such as survival, are warranted in order to fully investigate the therapeutic potential of quercetin in cancer cachexia.

Similar to quercetin, rutin, a quercetin glycoside more commonly seen in edible plants, has similar high bioavailability, making it a suitable candidate for nutritional therapy ^[46][86]. Supplementation with rutin (413 mg/kg/day) for 24 weeks increased survival in HPV16-tumor bearing mice and increased gastrocnemius muscle mass, which was associated with inhibition of NF-κB signaling ^[22][63]. Rutin also alleviated carcinogenesis via suppression of cyclo-oxygenase-2 in K14-HPV16 mice ^[47][87]. Studies have demonstrated the synergistic benefit of rutin in combination with chemotherapeutic drugs to further reduce cell proliferation in different cancer cell lines via activation of apoptosis, thereby enhancing the anti-cancer effect of chemotherapy ^[48][88]. Thus, rutin has significant potential in combination therapies to attenuate cancer cachexia.

Genistein and daidzein are isoflavones abundant in soy products, with anti-inflammatory and antioxidative properties ^[23][64]. Supplementation with soy isoflavones (mainly genistein and daidzein) for three weeks attenuated LLC tumor-induced muscle wasting by increasing both the overall muscle mass and size of individual muscle fibers within the gastrocnemius. These effects were associated with decreased expression of the ubiquitin-related E3 ligases, atrogin-1 and MuRF1, and likely mediated by ERK signaling to exert muscle-protecting function against cancer cachexia ^[23][64]. Soy isoflavones have also been widely discussed in the context of breast cancer, since they are plant-derived substances that activate signaling via estrogen receptors ^[49][89]. However, the benefit of soy isoflavones for breast cancer patients has been controversial ^[50][90]. In the MCF-7 breast cancer cell line, high dose (100 μM) of genistein combined with the chemotherapeutic agent, cisplatin, suppressed breast cancer cell growth and proliferation, whereas 10 μM of genistein antagonized the action of cisplatin to induce cancer cell apoptosis ^[49][89]. Further investigation confirmed that oral genistein supplementation (5 mg/kg/day) for three weeks counteracted cisplatin chemotherapy in breast cancer-bearing mice ^[51][91]. The anti-cancer effect of these soy isoflavones (genistein in particular) therefore remains controversial due to insufficient evidence. Such conflict raises doubt about the potential of these soy isoflavones to attenuate cancer-induced muscle atrophy. Future investigation is warranted to address these concerns.

Morin is a type of flavonoid, found in plants including Moraceae, Malpighiaceae, Myrtaceae, almond hulls and seaweeds ^[24][65]. Supplementation with a morin-rich diet for three weeks reduced tumor weight and progression in LLC-tumor bearing mice, demonstrating a powerful anti-cancer effect ^[24][65]. In addition, morin has been shown to have anti-cachectic potential, by attenuating cancer-induced muscle wasting in these same mice ^[24][65]. In vitro studies revealed that morin suppressed cancer cell growth via decreasing protein synthesis ^[24][65]. In contrast, morin (10 μM) increased protein synthesis in C2C12 myotubes, and this was associated with increased cell viability ^[24][65]. Moreover, oral morin treatment (50 mg/kg/day) for 30 days reduced the damage caused by a single injection of cisplatin in Sprague–Dawley rats by ameliorating chemotherapeutic drug-induced oxidative stress and activating antioxidant signaling cascades in isolated renal mitochondria ^[52][92]. These findings suggest a benefit for morin supplementation in reducing chemotherapy-induced cytotoxicity, which may also have positive effect on ameliorating chemotherapy-related oxidative stress in skeletal muscle. Further investigation is needed to evaluate the potential for morin to attenuate cancer cachexia.