Chemotherapy-induced Cachexia Research Articles

Sex differences in cachexia and branched-chain amino acid metabolism following chemotherapy in mice.

Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten-week-old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5-fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p < 0.05 for all). Drug treatment increased plasma BCAA only in males, but BCAA concentrations in the skeletal muscle of both sexes were decreased; this decrease was more profound in males (p = 0.0097). In addition, muscle expression of the BCAA transporter LAT1 was reduced; this reduction was more severe in females (p = 0.0264). In both sexes, the (inhibitory) phosphorylation of BCKD-E1αser293 was increased along with decreased BCKD activity. In the liver, drug treatment increased BCAA concentrations and LAT1 expression, but BCKD activity was suppressed in both sexes (p < 0.05 for all). Our results demonstrate that altered BCAA metabolism may contribute to chemotherapy-induced cachexia in a sex-dependent manner.

Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia.

Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.

Quercetin Improved Muscle Mass And Mitochondrial Content With Cancer And Chemotherapy-induced Cachexia

Quercetin Improved Muscle Mass And Mitochondrial Content With Cancer And Chemotherapy-induced Cachexia

Shenqi Fuzheng injection alleviates chemotherapy-induced cachexia by restoring glucocorticoid signaling in hypothalamus

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Probiotic OMNi-BiOTiC® 10 AAD Reduces Cyclophosphamide-Induced Inflammation and Adipose Tissue Wasting in Mice.

Cancer therapy is often associated with severe side effects such as drug induced weight loss, also known as chemotherapy-induced cachexia. The aim of this study was to investigate the effects of a multispecies probiotic (OMNi-BiOTiC® 10 AAD) in a chemotherapy mouse model. A total of 24 male BALB/c mice were gavage-fed with the probiotic formulation or water, once a day for 3 weeks. In the third week, the mice received intraperitoneal cyclophosphamide. At euthanasia, the organs were dissected, and serum was sampled for cytokine analysis. Tight junction components, myosin light chain kinase, mucins, and apoptosis markers were detected in the ileum and colon using histological analyses and qRT-PCR. Lipolysis was analyzed by enzymatic activity assay, Western blotting analyses, and qRT-PCR in WAT. The fecal microbiome was measured with 16S-rRNA gene sequencing from stool samples, and fecal volatile organic compounds analysis was performed using gas chromatography/mass spectrometry. The probiotic-fed mice exhibited significantly less body weight loss and adipose tissue wasting associated with a reduced CGI58 mediated lipolysis. They showed significantly fewer pro-inflammatory cytokines and lower gut permeability compared to animals fed without the probiotic. The colons of the probiotic-fed animals showed lower inflammation scores and less goblet cell loss. qRT-PCR revealed no differences in regards to tight junction components, mucins, or apoptosis markers. No differences in microbiome alpha diversity, but differences in beta diversity, were observed between the treatment groups. Taxonomic analysis showed that the probiotic group had a lower relative abundance of Odoribacter and Ruminococcus-UCG014 and a higher abundance of Desulfovibrio. VOC analysis yielded no significant differences. The results of this study indicate that oral administration of the multispecies probiotic OMNi-BiOTiC® 10 AAD could mitigate cyclophosphamide-induced chemotherapy side effects.

Proteomic analysis reveals that Polygonatum cyrtonema Hua polysaccharide ameliorates mice muscle atrophy in chemotherapy-induced cachexia

Polygonatum cyrtonema Hua polysaccharide (PCP) is the main bioactive compound derived from the herb Polygonati Rhizoma, known for its anti-fatigue, antioxidant, immunomodulatory, and anti-inflammatory properties. However, its effectiveness on alleviating chemotherapy-induced muscle atrophy has been unclear. In this study, we utilized proteomic analysis to investigate the effects and mechanisms of PCP on gemcitabine plus cisplatin (GC) induced muscle atrophy in mice. Quality control analysis revealed that the functional PCP, rich in glucose, is a heterogeneous polysaccharide comprised of nine monosaccharides. PCP (64 mg/kg) significantly alleviated body muscle, organ weight loss, and muscle fiber atrophy in chemotherapy-induced cachectic mice. Moreover, PCP suppressed the decrease in serum immunoglobulin levels and the increase in pro-inflammatory factor interleukin-6 (IL-6). Proteomic analysis demonstrated that PCP contributed to the homeostasis of protein metabolism in gastrocnemius muscle. Diacylglycerol kinase (DGKζ) and cathepsin L (CTSL) were identified as primary PCP targets. Furthermore, the IL-6/STAT3/CTSL and DGKζ/FoxO/Atrogin1 signaling pathways were validated. Our findings suggest that PCP exerts an anti-atrophy effect on chemotherapy-induced muscle atrophy by regulating the autophagy-lysosome and ubiquitin-proteasome systems.

Polysaccharide of Ganoderma lucidum Ameliorates Cachectic Myopathy Induced by the Combination Cisplatin plus Docetaxel in Mice.

Cachexia is a lethal muscle-wasting syndrome associated with cancer and chemotherapy use. Mounting evidence suggests a correlation between cachexia and intestinal microbiota, but there is presently no effective treatment for cachexia. Whether the Ganoderma lucidum polysaccharide Liz-H exerts protective effects on cachexia and gut microbiota dysbiosis induced by the combination cisplatin plus docetaxel (cisplatin + docetaxel) was investigated. C57BL/6J mice were intraperitoneally injected with cisplatin + docetaxel, with or without oral administration of Liz-H. Body weight, food consumption, complete blood count, blood biochemistry, and muscle atrophy were measured. Next-generation sequencing was also performed to investigate changes to gut microbial ecology. Liz-H administration alleviated the cisplatin + docetaxel-induced weight loss, muscle atrophy, and neutropenia. Furthermore, upregulation of muscle protein degradation-related genes (MuRF-1 and Atrogin-1) and decline of myogenic factors (MyoD and myogenin) after treatment of cisplatin and docetaxel were prevented by Liz-H. Cisplatin and docetaxel treatment resulted in reducing comparative abundances of Ruminococcaceae and Bacteroides, but Liz-H treatment restored these to normal levels. This study indicates that Liz-H is a good chemoprotective reagent for cisplatin + docetaxel-induced cachexia. IMPORTANCE Cachexia is a multifactorial syndrome driven by metabolic dysregulation, anorexia, systemic inflammation, and insulin resistance. Approximately 80% of patients with advanced cancer have cachexia, and cachexia is the cause of death in 30% of cancer patients. Nutritional supplementation has not been shown to reverse cachexia progression. Thus, developing strategies to prevent and/or reverse cachexia is urgent. Polysaccharide is a major biologically active compound in the fungus Ganoderma lucidum. This study is the first to report that G. lucidum polysaccharides could alleviate chemotherapy-induced cachexia via reducing expression of genes that are known to drive muscle wasting, such as MuRF-1 and Atrogin-1. These results suggest that Liz-H is an effective treatment for cisplatin + docetaxel-induced cachexia.

Cytarabine induces cachexia with lipid malabsorption via zippering the junctions of lacteal in murine small intestine

Chemotherapy-induced cachexia causes severe metabolic abnormalities independently of cancer and reduces the therapeutic efficacy of chemotherapy. The underlying mechanism of chemotherapy-induced cachexia remains unclear. Here we investigated the cytarabine (CYT)-induced alteration in energy balance and its underlying mechanisms in mice. We compared energy balance-associated parameters among the three groups of mice: CON, CYT, and PF (pair-fed mice with the CYT group) that were intravenously administered vehicle or CYT. Weight gain, fat mass, skeletal muscle mass, grip strength, and nocturnal energy expenditure were significantly lowered in the CYT group than in the CON and PF groups. The CYT group demonstrated less energy intake than the CON group and higher respiratory quotient than the PF group, indicating that CYT induced cachexia independently from the anorexia-induced weight loss. Serum triglyceride was significantly lower in the CYT group than in the CON group, whereas the intestinal mucosal triglyceride levels and the lipid content within the small intestine enterocyte were higher after lipid loading in the CYT group than in the CON and PF groups, suggesting that CYT inhibited lipid uptake in the intestine. This was not associated with obvious intestinal damage. The CYT group showed increased zipper-like junctions of lymphatic endothelial vessel in duodenal villi compared to that in the CON and CYT groups, suggesting their imperative role in the CYT-induced inhibition of lipid uptake. CYT worsens cachexia independently of anorexia by inhibiting the intestinal lipid uptake, via the increased zipper-like junctions of lymphatic endothelial vessel.

Unexpected worsening of doxorubicin cardiotoxicity upon intermittent fasting

Recently in Cell Metabolism, Ozcan etal. used preclinical and clinical data to suggest that alternate-day fasting may exacerbate the cardiotoxic effects of doxorubicin through the TFEB/GDF15 pathway, leading to myocardial atrophy and impaired cardiac function. The link between caloric intake, chemotherapy-induced cachexia, and cardiotoxicity warrants more clinical attention.

GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice.

Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice. Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (n=10-16 mice per group). A11 was administered subcutaneously (10mg/kg) 1day before intraperitoneal treatment with cisplatin (10mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis. A11 reduced serum response element-luciferase reporter activity up to 74% (P<0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P=0.0593), AKT phosphorylation up to 28% (P=0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P=0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P<0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P<0.05) and tumour-free body weight loss by 13% (P<0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P<0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P<0.05). Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy-induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy-induced cachexia.

NAD+ repletion with niacin counteracts cancer cachexia

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.

Targeting Mitochondria and Oxidative Stress in Cancer- and Chemotherapy-Induced Muscle Wasting.

Significance: Cancer is frequently associated with the early appearance of cachexia, a multifactorial wasting syndrome. If not present at diagnosis, cachexia develops either as a result of tumor progression or as a side effect of anticancer treatments, especially of standard chemotherapy, eventually representing the direct cause of death in up to one-third of all cancer patients. Cachexia, within its multiorgan affection, is characterized by severe loss of muscle mass and function, representing the most relevant subject of preclinical and clinical investigation. Recent Advances: The pathogenesis of muscle wasting in cancer- and chemotherapy-induced cachexia is complex, and encompasses heightened protein catabolism and reduced anabolism, disrupted mitochondria and energy metabolism, and even neuromuscular junction dismantling. The mechanisms underlying these alterations are still controversial, especially concerning the molecular drivers that could be targeted for anticachexia therapies. Inflammation and mitochondrial oxidative stress are among the principal candidates; the latter being extensively discussed in the present review. Critical Issues: Several approaches have been tested to modulate the redox homeostasis in tumor hosts, and to counteract cancer- and chemotherapy-induced muscle wasting, from exercise training to distinct classes of direct or indirect antioxidants. We herein report the most relevant results obtained from both preclinical and clinical trials. Future Directions: Including the assessment and the treatment of altered redox balance in the clinical management of cancer patients is still a big challenge. The available evidence suggests that fortifying the antioxidant defenses by either pharmacological or nonpharmacological strategies will likely improve cachexia and eventually the outcome of a broad cancer patient population. Antioxid. Redox Signal. 38, 352-370.

Quercetin Improved Muscle Mass and Mitochondrial Content in a Murine Model of Cancer and Chemotherapy-Induced Cachexia.

A cachexia diagnosis is associated with a doubling in hospital stay and increased healthcare cost for cancer patients and most cachectic patients do not survive treatment. Unfortunately, complexity in treating cachexia is amplified by both the underlying malignancy and the anti-cancer therapy which can independently promote cachexia. Quercetin, an organic polyphenolic flavonoid, has demonstrated anti-inflammatory and antioxidant properties with promise in protecting against cancer and chemotherapy-induced dysfunction; however, whether quercetin is efficacious in maintaining muscle mass in tumor-bearing animals receiving chemotherapy has not been investigated. C26 tumor-bearing mice were given 5-fluorouracil (5FU; 30 mg/kg of lean mass i.p.) concomitant with quercetin (Quer; 50 mg/kg of body weight via oral gavage) or vehicle. Both C26 + 5FU and C26 + 5FU + Quer had similar body weight loss; however, muscle mass and cross-sectional area was greater in C26 + 5FU + Quer compared to C26 + 5FU. Additionally, C26 + 5FU + Quer had a greater number and larger intermyofibrillar mitochondria with increased relative protein expression of mitochondrial complexes V, III, and II as well as cytochrome c expression. C26 + 5FU + Quer also had increased MFN1 and reduced FIS1 relative protein expression without apparent benefits to muscle inflammatory signaling. Our data suggest that quercetin protected against cancer and chemotherapy-induced muscle mass loss through improving mitochondrial homeostatic balance.

Interruption of the long non-coding RNA HOTAIR signaling axis ameliorates chemotherapy-induced cachexia in bladder cancer

BackgroundCisplatin-based chemotherapy is the first line of treatment for bladder cancer. However, cisplatin induces muscle wasting associated with NF-κB and cancer cachexia. HOTAIR, an oncogenic long non-coding RNA (lncRNA), promotes cancer progression in different cancers. Crosstalk between HOTAIR and NF-κB is documented. Prothymosin α (ProT) plays important roles in cancer progression and inflammation. However, the potential link between HOTAIR, ProT, and cisplatin-induced cancer cachexia remains unexplored. Here, we investigated the contribution of HOTAIR in cisplatin-induced cancer cachexia and dissected the potential signaling cascade involving the epidermal growth factor receptor (EGFR), ProT, NF-κB, and HOTAIR.Materials and methodsExpression of ProT and HOTAIR transcripts and their correlations in tumor tissues of bladder cancer patients and bladder cancer cell lines were determined by RT-qPCR. Next, levels of phospho-EGFR, EGFR, phospho-NF-κB, and NF-κB were examined by immunoblot analysis in human bladder cancer cells treated with cisplatin. Expression of HOTAIR in cisplatin-treated cells was also assessed by RT-qPCR. Pharmacological inhibitors and overexpression and knockdown approaches were exploited to decipher the signaling pathway. The murine C2C12 myoblasts were used as an in vitro muscle atrophy model. The syngeneic murine MBT-2 bladder tumor was used to investigate the role of mouse Hotair in cisplatin-induced cancer cachexia.ResultsExpression of ProT and HOTAIR was higher in bladder tumors than in normal adjacent tissues. There were positive correlations between ProT and HOTAIR expression in clinical bladder tumors and bladder cancer cell lines. Cisplatin treatment increased EGFR and NF-κB activation and upregulated ProT and HOTAIR expression in bladder cancer cells. ProT overexpression increased, whereas ProT knockdown decreased, HOTAIR expression. Notably, cisplatin-induced HOTAIR upregulation was abrogated by EGFR inhibitors or ProT knockdown. ProT-induced HOTAIR overexpression was diminished by NF-κB inhibitors. HOTAIR overexpression enhanced, whereas its knockdown reduced, cell proliferation, cachexia-associated pro-inflammatory cytokine expression, and muscle atrophy. Cachexia-associated symptoms were ameliorated in mice bearing Hotair-knockdown bladder tumors undergoing cisplatin treatment.ConclusionsWe demonstrate for the first time a critical role for HOTAIR and identify the involvement of the EGFR-ProT-NF-κB-HOTAIR signaling axis in cisplatin-induced cachexia in bladder cancer and likely other cancers. Our findings also provide therapeutic targets for this disease.

Obesity reduced survival with 5-fluorouracil and did not protect against chemotherapy-induced cachexia or immune cell cytotoxicity in mice

ABSTRACT Fluorouracil/5-flourouracil (5FU) is a first-line chemotherapy drug for many cancer types; however, its associated toxicities contribute to poor quality of life and reduced dose intensities negatively impacting patient prognosis. While obesity remains a critical risk factor for most cancers, our understanding regarding how obesity may impact chemotherapy’s toxicities is extremely limited. C56BL/6 mice were given high fat (Obese) or standard diets (Lean) for 4 months and then subjected to three cycles of 5FU (5d-40 mg/kg Lean Mass, 9d rest) or PBS vehicle control. Shockingly, only 60% of Obese survived 3 cycles compared to 100% of Lean, and Obese lost significantly more body weight. Dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5FU catabolism, was reduced in obese livers. Total white blood cells, neutrophils, and lymphocytes were reduced in Obese 5FU compared to Lean 5FU and PBS controls. While adipocyte size was not affected by 5FU in Obese, skeletal muscle mass and myofibrillar cross section area were decreased following 5FU in Lean and Obese. Although adipose tissue inflammatory gene expression was not impacted by 5FU, distinct perturbations to skeletal muscle inflammatory gene expression and immune cell populations (CD45+ Immune cells, CD45+CD11b+CD68+ macrophages and CD45+CD11b+Ly6clo/int macrophage/monocytes) were observed in Obese only. Our evidence suggests that obesity induced liver pathologies and reduced DPD exacerbated 5FU toxicities. While obesity has been suggested to protect against cancer/chemotherapy-induced cachexia and other toxicities, our results demonstrate that obese mice are not protected, but rather show evidence of increased susceptibility to 5FU-induced cytotoxicity even when dosed for relative lean mass.

Chemotherapy Drugs Induce Cachexia and Alter Muscle Protein Metabolism

Chemotherapy is the main regimen to treat neoplastic tumours. Maintenance of muscle mass during treatment is associated with greater patient prognosis and reduces toxicity and severe side effects. However, chemotherapy induces cachexia, a wasting disorder characterized by muscle weakness and a loss of muscle mass. Although cancer, a disease treated with chemotherapy, is often diagnosed in older individuals, studies investigating chemotherapy‐induced cachexia are done exclusively in young animals at an age equivalent to a 20‐year‐old human. Therefore, studies investigating the effects of chemotherapy‐induced cachexia at an age range relevant to humans is needed. The objective of this study is to compare the severity and mechanisms of chemotherapy‐induced cachexia in 3‐month‐old adult (equivalent to a 20‐year‐old human) and 18‐month‐old (equivalent to a 56‐year‐old human) mice. Three‐month‐old adult CD2F1 male mice were treated with either folfiri (50mg/kg 5‐fluorouracil (5FU), 90mg/kg Leucovorin and 24mg/kg CPT11) (drug) or vehicle (10% DMSO in saline) for 6‐weeks. Male mice aged to 18‐months will undergo similar treatments. Adult mice treated with the drug cocktail exhibited significant body weight loss (~10%, n=4, p=0.0117) with no differences in food intake. Decreases in body weight were associated with a loss of muscle mass in the gastrocnemius (~25%, n=4, p=0.006), quadriceps (~30%, n=4, p=0.019) and tibialis anterior (~40%, n=4, p&lt;0.0001). Insulin tolerance tests at weeks 3 and 6 of treatment were also performed and glucose levels were found to be non‐significantly higher in drug‐treated mice. Signalling factors related to the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), protein synthesis, autophagy and the ubiquitin proteasome system will be measured. Key enzymes responsible for the breakdown of the branched chain amino acids (BCAAs), mainly branched‐chain alpha‐ketoacid dehydrogenase complex (BCKD) and branched‐chain amino acid transferase 2 (BCAT2) will also be measured in the skeletal muscle. Along this line, in cell culture, we have previously shown decreased (~20%) activity of the BCKD enzyme, corresponding with decreased amino acid concentrations of leucine (~40%), isoleucine (~60%), valine (~50%), alanine (~30%), arginine (~60%), phenylalanine (50%), serine (50%) and glutamate (50%) in chemotherapy‐treated myotubes. We also observed decreased (~65%) expression of amino acid transporters sodium‐coupled neutral amino acid transporter 1 (SNAT1) and large neutral amino acid transporter 1 (LAT1). Timepoint analysis showed SNAT1 expression to be decreased prior to decreases in BCKD activity, signifying that alterations in BCAA metabolism may be a result of decreased levels of BCAAs and amino acids in chemotherapy‐treated myotubes. Therefore, these findings stemmed our interest in how the BCAAs, and their metabolites are affected in‐vivofollowing chemotherapy treatment. Findings from this study will help to elucidate whether unique signatures of cachexia are experienced in older mice. Better understanding of the mechanisms underlying muscle mass regulation following chemotherapy treatment may help combat cachexia.

PLAG alleviates cisplatin-induced cachexia in lung cancer implanted mice

Chemotherapy-induced cachexia has been a significant challenge to the successful treatment of cancer patients. Chemotherapy leads to loss of muscle, loss of appetite, and excessive weight loss, which makes these necessary treatments intolerable for most patients. Therefore, it is necessary to alleviate cachexia to successfully treat cancer patients.In this study, tumor-implanted mouse models administered cisplatin showed rapid weight loss and reduced feeding rate by the second week of treatment, and 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) effectively alleviated cisplatin-induced cachexia. In mice treated with cisplatin on a sacrificial day after 6 weeks, the weight of the two major leg muscles (quadriceps femoris and gastrocnemius) were reduced by up to 70%, but this muscle reduction was successfully prevented in the PLAG co-treatment group. The distribution and size of muscle fibers that appear in small units in cisplatin-treated mice were restored to normal levels by PLAG co-treatment. Furthermore, myostatin expression levels were upregulated by cisplatin, whereas myostatin decreased to normal levels with muscle recovery in the PLAG co-treated group. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which are commonly expressed in cachexia, were significantly increased in cisplatin-treated mice but were reduced to normal levels in PLAG co-treated mice. Glucose absorption, an indicator of muscle tissue activity, decreased with cisplatin treatment and recovered to normal levels with PLAG co-treatment. Overall, PLAG effectively alleviated cisplatin-induced cachexia symptoms and reduced tumor growth in tumor-implanted mice.These findings suggest PLAG may be a promising drug to alleviate cachexia in cancer patients receiving chemotherapy.

Chemotherapy-induced cachexia and model-informed dosing to preserve lean mass in cancer treatment.

Although chemotherapy is a standard treatment for cancer, it comes with significant side effects. In particular, certain agents can induce severe muscle loss, known as cachexia, worsening patient quality of life and treatment outcomes. 5-fluorouracil, an anti-cancer agent used to treat several cancers, has been shown to cause muscle loss. Experimental data indicates a non-linear dose-dependence for muscle loss in mice treated with daily or week-day schedules. We present a mathematical model of chemotherapy-induced muscle wasting that captures this non-linear dose-dependence. Area-under-the-curve metrics are proposed to quantify the treatment’s effects on lean mass and tumour control. Model simulations are used to explore alternate dosing schedules, aging effects, and morphine use in chemotherapy treatment with the aim of better protecting lean mass while actively targeting the tumour, ultimately leading to improved personalization of treatment planning and improved patient quality of life.

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere.

Simple SummaryIn addition to cancer-related factors, anti-cancer chemotherapy treatment can drive life-threatening body wasting in a syndrome known as cachexia. Emerging evidence has described the impact of several key chemotherapeutic agents on skeletal muscle in particular, and the mechanisms are gradually being unravelled. Despite this evidence, there remains very little research regarding therapeutic strategies to protect muscle during anti-cancer treatment and current global grand challenges focused on deciphering the cachexia conundrum fail to consider this aspect—chemotherapy-induced myopathy remains very much on the dark side of the cachexia sphere. This review explores the impact and mechanisms of, and current investigative strategies to protect against, chemotherapy-induced myopathy to illuminate this serious issue.Cancer cachexia is a debilitating multi-factorial wasting syndrome characterised by severe skeletal muscle wasting and dysfunction (i.e., myopathy). In the oncology setting, cachexia arises from synergistic insults from both cancer–host interactions and chemotherapy-related toxicity. The majority of studies have surrounded the cancer–host interaction side of cancer cachexia, often overlooking the capability of chemotherapy to induce cachectic myopathy. Accumulating evidence in experimental models of cachexia suggests that some chemotherapeutic agents rapidly induce cachectic myopathy, although the underlying mechanisms responsible vary between agents. Importantly, we highlight the capacity of specific chemotherapeutic agents to induce cachectic myopathy, as not all chemotherapies have been evaluated for cachexia-inducing properties—alone or in clinically compatible regimens. Furthermore, we discuss the experimental evidence surrounding therapeutic strategies that have been evaluated in chemotherapy-induced cachexia models, with particular focus on exercise interventions and adjuvant therapeutic candidates targeted at the mitochondria.

Metronomic 5-Fluorouracil Delivery Primes Skeletal Muscle for Myopathy but Does Not Cause Cachexia.

Skeletal myopathy encompasses both atrophy and dysfunction and is a prominent event in cancer and chemotherapy-induced cachexia. Here, we investigate the effects of a chemotherapeutic agent, 5-fluorouracil (5FU), on skeletal muscle mass and function, and whether small-molecule therapeutic candidate, BGP-15, could be protective against the chemotoxic challenge exerted by 5FU. Additionally, we explore the molecular signature of 5FU treatment. Male Balb/c mice received metronomic tri-weekly intraperitoneal delivery of 5FU (23 mg/kg), with and without BGP-15 (15 mg/kg), 6 times in total over a 15 day treatment period. We demonstrated that neither 5FU, nor 5FU combined with BGP-15, affected body composition indices, skeletal muscle mass or function. Adjuvant BGP-15 treatment did, however, prevent the 5FU-induced phosphorylation of p38 MAPK and p65 NF-B subunit, signalling pathways involved in cell stress and inflammatory signalling, respectively. This as associated with mitoprotection. 5FU reduced the expression of the key cytoskeletal proteins, desmin and dystrophin, which was not prevented by BGP-15. Combined, these data show that metronomic delivery of 5FU does not elicit physiological consequences to skeletal muscle mass and function but is implicit in priming skeletal muscle with a molecular signature for myopathy. BGP-15 has modest protective efficacy against the molecular changes induced by 5FU.