ABSTRACT
Cancer cachexia, or the unintentional loss of body weight in patients with cancer, is a multiorgan and multifactorial syndrome with a complex and largely unknown etiology; however, metabolic dysfunction and inflammation remain hallmarks of cancer-associated wasting. Although cachexia manifests with muscle and adipose tissue loss, perturbations to the gastrointestinal tract may serve as the frontline for both impaired nutrient absorption and immune-activating gut dysbiosis. Investigations into the gut microbiota have exploded within the past two decades, demonstrating multiple gut-tissue axes; however, the link between adipose and skeletal muscle wasting and the gut microbiota with cancer is only beginning to be understood. Furthermore, the most used anticancer drugs (e.g. chemotherapy and immune checkpoint inhibitors) negatively impact gut homeostasis, potentially exacerbating wasting and contributing to poor patient outcomes and survival. In this review, we 1) highlight our current understanding of the microbial changes that occur with cachexia, 2) discuss how microbial changes may contribute to adipose and skeletal muscle wasting, and 3) outline study design considerations needed when examining the role of the microbiota in cancer-induced cachexia.
Subject(s)
Cachexia , Gastrointestinal Microbiome , Muscle, Skeletal , Neoplasms , Cachexia/metabolism , Cachexia/microbiology , Cachexia/etiology , Humans , Gastrointestinal Microbiome/physiology , Neoplasms/microbiology , Neoplasms/complications , Neoplasms/metabolism , Animals , Muscle, Skeletal/metabolism , Muscle, Skeletal/microbiology , Dysbiosis/microbiology , Adipose Tissue/metabolism , Adipose Tissue/microbiology , Adipose Tissue/immunologyABSTRACT
Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness: whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (-15%; P = 0.006), contact length (-38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.NEW & NOTEWORTHY We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.
Subject(s)
Cachexia , Carcinoma, Lewis Lung , Lipid Droplets , Mice, Inbred C57BL , Muscle, Skeletal , Animals , Cachexia/metabolism , Cachexia/pathology , Cachexia/etiology , Male , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Carcinoma, Lewis Lung/complications , Lipid Droplets/metabolism , Lipid Droplets/pathology , Mice , Lipid Metabolism , Mitochondria, Muscle/metabolism , Mitochondria, Muscle/pathology , Mitochondria, Muscle/ultrastructure , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/ultrastructureABSTRACT
Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol-a novel, potent, bioavailable compound found in American ginseng-can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. Fourteen-week-old C57BL/6 female mice were either given three rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or one round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage three times per week for the study duration. Consistent with our previous findings, panaxynol significantly (P < 0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (P < 0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16S Sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). In addition, panaxynol significantly (P < 0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into the mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.NEW & NOTEWORTHY In the current study, we report that panaxynol ameliorates chemically induced murine colitis by improving colonic crypt and mucosal architecture, suppressing colitis-enriched microbes, reducing macrophages, and promoting the differentiation of regulatory T-cells in the colonic lamina propria. This study suggests that this novel natural compound may serve as a safe and effective treatment option for colitis patients.
Subject(s)
Colitis , Dextran Sulfate , Gastrointestinal Microbiome , Intestinal Mucosa , Mice, Inbred C57BL , Animals , Female , Mice , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Mucosa/microbiology , Intestinal Mucosa/immunology , Gastrointestinal Microbiome/drug effects , Colitis/drug therapy , Colitis/chemically induced , Colitis/pathology , Colitis/immunology , Colitis/microbiology , Fatty Alcohols/pharmacology , Diynes/pharmacology , Disease Models, Animal , Colon/drug effects , Colon/pathology , Colon/immunology , Colon/microbiology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/pathology , Colitis, Ulcerative/microbiologyABSTRACT
Immune cell-driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy-induced cachexia. CD2F1 mice were given 106 C26 cells, followed by five doses of 5-fluorouracil (5FU; 30 mg/kg LM, ip) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. Although 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26 + 5FU. C26 increased CD11b+Ly6g+ and CD11b+Ly6cInt inflammatory myeloid cells in SKM and AT; however, both populations were reduced with C26 + 5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26 + 5FU. C26 + 5FU increased SKM CD11b-CD11c+ dendritic cells, CD11b-NK1.1+ NK-cells, and CD11b-B220+ B-cells, and reduced Ly6cHiCX3CR1+CD206+CD163IntCD11c-MHCII- infiltrated macrophages and other CD11b+Ly6cHi myeloid cells compared with C26. Both C26 and C26 + 5FU had elevated CD11b+F480+CD206+MHCII- or more specifically Ly6cLoCX3CR1+CD206+CD163IntCD11c-MHCII- profibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, profibrotic cells and muscle inflammatory/atrophic signaling appear consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets.NEW & NOTEWORTHY Despite being an immune-driven condition, our understanding of skeletal muscle and adipose tissue immune cells with cachexia is limited. Here, we identified immune cell populations in tumors, skeletal muscle, and adipose tissue in C26 tumor-bearing mice with/without 5-fluorouracil (5FU). C26 and C26 + 5FU had increased skeletal muscle profibrotic macrophages, but 5FU reduced inflammatory myeloid cells without sparing mass. Tumor presence and chemotherapy have contrasting effects on certain immune cells, which appeared not necessary for wasting.
Subject(s)
Antineoplastic Agents , Fluorouracil , Mice , Animals , Fluorouracil/adverse effects , Cachexia/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy/pathology , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND: More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia. METHODS: Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high-resolution respirometry and transmission electron microscopy (TEM). RESULTS: Obese LLC mice experienced significant tumour-free body weight loss similar to lean (-12.8% vs. -11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2 = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (-24%, P < 0.0354) and mCSA (-16%, P = 0.0004) with similar activation of muscle p65 (P = 0.0337), and p38 (P = 0.0008). ADP-dependent coupled respiration was reduced in both Obese and Obese LLC muscle (-30%, P = 0.0072) consistent with reductions in volitional cage activity (-39%, P < 0.0001) and grip strength (-41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: -37%, P = 0.0009; SS: -21%, P = 0.0101) and LLC (IMF: -40%, P = 0.0019; SS: -27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 (P = 0.0029) and DRP1 (P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 (P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle. CONCLUSIONS: Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre-existing metabolic conditions when determining the impact of weight status on cancer-induced cachexia and functional mitochondrial deficits.
Subject(s)
Cachexia , Carcinoma, Lewis Lung , Humans , Male , Animals , Mice , Cachexia/pathology , Mice, Inbred C57BL , Mitochondria/metabolism , Muscular Atrophy/pathology , Carcinoma, Lewis Lung/complications , Carcinoma, Lewis Lung/pathology , Obesity/complications , Obesity/pathology , Muscle, Skeletal/pathologyABSTRACT
It has been suspected that tumor resection surgery itself may accelerate breast cancer (BC) lung metastasis in some patients. Emodin, a natural anthraquinone found in the roots and rhizomes of various plants, exhibits anticancer activity. We examined the perioperative use of emodin in our established surgery wounding murine BC model. Emodin reduced primary BC tumor growth and metastasis in the lungs in both sham and surgical wounded mice, consistent with a reduction in proliferation and enhanced apoptosis (primary tumor and lungs). Further, emodin reduced systemic inflammation, most notably the number of monocytes in the peripheral blood and reduced pro-tumoral M2 macrophages in the primary tumor and the lungs. Consistently, we show that emodin reduces gene expression of select macrophage markers and associated cytokines in the primary tumor and lungs of wounded mice. Overall, we demonstrate that emodin is beneficial in mitigating surgical wounding accelerated lung metastasis in a model of triple-negative BC, which appears to be mediated, at least in part, by its actions on macrophages. These data support the development of emodin as a safe, low-cost, and effective agent to be used perioperatively to alleviate the surgery triggered inflammatory response and consequential metastasis of BC to the lungs.
Subject(s)
Emodin , Lung Neoplasms , Triple Negative Breast Neoplasms , Humans , Animals , Mice , Emodin/pharmacology , Emodin/therapeutic use , Emodin/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Macrophages/metabolism , Lung/metabolism , Cell Line, TumorABSTRACT
Currently available colorectal cancer (CRC) therapies have limited efficacy and severe adverse effects that may be overcome with the alternative use of natural compounds. We previously reported that panaxynol (PA), a bioactive component in American ginseng, possesses anticancer properties in vitro and suppresses murine colitis through its proapoptotic and anti-inflammatory properties. Because colitis is a predisposing factor of CRC and inflammation is a major driver of CRC, we sought to evaluate the therapeutic potential of PA in CRC. Azoxymethane-dextran sodium sulfate (AOM/DSS) mice (C57BL/6) were administered 2.5 mg/kg PA or vehicle 3 times/wk via oral gavage over 12 wk. PA improved clinical symptoms (P ≤ 0.05) and reduced tumorigenesis (P ≤ 0.05). This improvement may be reflective of PA's restorative effect on intestinal barrier function; PA upregulated the expression of essential tight junction and mucin genes (P ≤ 0.05) and increased the abundance of mucin-producing goblet cells (P ≤ 0.05). Given that macrophages play a substantial role in the pathogenesis of CRC and that we previously demonstrated that PA targets macrophages in colitis, we next assessed macrophages. We show that PA reduces the relative abundance of colonic macrophages within the lamina propria (P ≤ 0.05), and this was consistent with a reduction in the expression of important markers of macrophages and inflammation (P ≤ 0.05). We further confirmed PA's inhibitory effects on macrophages in vitro under CRC conditions (P ≤ 0.05). These results suggest that PA is a promising therapeutic compound to treat CRC and improve clinical symptoms given its ability to inhibit macrophages and modulate the inflammatory environment in the colon.NEW & NOTEWORTHY We report that panaxynol (PA) reduces colorectal cancer (CRC) by improving the colonic and tumor environment. Specifically, we demonstrate that PA improves crypt morphology, upregulates crucial tight junction and mucin genes, and promotes the abundance of mucin-producing goblet cells. Furthermore, PA reduces macrophages and associated inflammation, important drivers of CRC, in the colonic environment. This present study provides novel insights into the potential of PA as a therapeutic agent to ameliorate CRC tumorigenesis.
Subject(s)
Colitis , Colorectal Neoplasms , Mice , Animals , Disease Models, Animal , Mice, Inbred C57BL , Inflammation/metabolism , Colitis/chemically induced , Colitis/drug therapy , Colitis/metabolism , Carcinogenesis/metabolism , Cell Transformation, Neoplastic/metabolism , Azoxymethane/metabolism , Azoxymethane/pharmacology , Azoxymethane/therapeutic use , Macrophages/metabolism , Colorectal Neoplasms/metabolism , Mucins/metabolism , Dextran Sulfate/pharmacologyABSTRACT
Approximately one-third of all breast cancer mortality results from metastatic recurrence after initial success of surgery and/or therapy. Although primary tumor removal is widely accepted as beneficial, it has long been suspected that surgery itself contributes to accelerated metastatic recurrence. We investigated surgical wounding's impact on tumor progression and lung metastasis in a murine model of triple negative breast cancer (TNBC). Ten-week-old female mice were inoculated with 4 T1 cells (week 0) and were either subjected to a 2 cm long cutaneous contralateral incision (wounded) or control (non-wounded) on week 2 and monitored for 3 weeks (week 5). Mice with surgical wounding displayed significantly accelerated tumor growth observable as early as 1-week post wounding. This was confirmed by increased tumor volume and tumor weight, post-mortem. Further, surgical wounding increased metastasis to the lungs, as detected by IVIS imaging, in vivo and ex vivo (week 5). As expected then, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. Flow cytometry revealed that primary tumors from wounded mice exhibited increased tumor associated macrophages and specifically M2-like macrophages, which are important in promoting tumor development, maintenance, and metastasis. Immunofluorescence staining and gene expression data further confirms an increase in macrophages in both the primary tumor and the lungs of wounded mice. Our data suggests that surgical wounding accelerates tumor progression and lung metastasis in a mouse model of TNBC, which is likely mediated, at least in part by an increase in macrophages.
Subject(s)
Lung Neoplasms , Triple Negative Breast Neoplasms , Humans , Mice , Female , Animals , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Disease Models, Animal , Cell Line, Tumor , Macrophages/metabolismABSTRACT
Ulcerative colitis (UC) is a chronic disease that is characterized by diffuse inflammation of the colonic and rectal mucosa. The burden of UC is rising globally with significant disparities in levels and trends of disease in different countries. The pathogenesis of UC involves the presence of pathogenic factors including genetic, environmental, autoimmune, and immune-mediated components. Evidence suggests that disturbed interactions between the host immune system and gut microbiome contribute to the origin and development of UC. Current medications for UC include antibiotics, corticosteroids, and biological drugs, which can have deleterious off-target effects on the gut microbiome, contributing to increased susceptibility to severe infections and chronic immunosuppression. Alternative, nonpharmacological, and behavioral interventions have been proposed as safe and effective treatments to alleviate UC, while also holding the potential to improve overall life quality. This mini-review will discuss the interactions between the immune system and the gut microbiome in the case of UC. In addition, we suggest nonpharmacological and behavioral strategies aimed at restoring a proper microbial-immune relationship.
Subject(s)
Colitis, Ulcerative , Gastrointestinal Microbiome , Humans , Colitis, Ulcerative/pathology , Homeostasis , ImmunityABSTRACT
5-Fluorouracil (5FU) remains a first-line chemotherapeutic for several cancers despite its established adverse side effects. Reduced blood counts with cytotoxic chemotherapies not only expose patients to infection and fatigue, but can disrupt tissue repair and remodeling, leading to lasting functional deficits. We sought to characterize the impact of 5FU-induced leukopenia on skeletal muscle in the context of remodeling. First, C57BL/6 mice were subjected to multiple dosing cycles of 5FU and skeletal muscle immune cells were assessed. Second, mice given 1 cycle of 5FU were subjected to 1.2% BaCl2 intramuscularly to induce muscle damage. One cycle of 5FU induced significant body weight loss, but only three dosing cycles of 5FU induced skeletal muscle mass loss. One cycle of 5FU reduced skeletal muscle CD45+ immune cells with a particular loss of infiltrating CD11b+Ly6cHi monocytes. Although CD45+ cells returned following three cycles, CD11b+CD68+ macrophages were reduced with three cycles and remained suppressed at 1 mo following 5FU administration. One cycle of 5FU blocked the increase in CD45+ immune cells 4 days following BaCl2; however, there was a dramatic increase in CD11b+Ly6g+ neutrophils and a loss of CD11b+Ly6cHi monocytes in damaged muscle with 5FU compared with PBS. These perturbations resulted in increased collagen production 14 and 28 days following BaCl2 and a reduction in centralized nuclei and myofibrillar cross-sectional area compared with PBS. Together, these results demonstrate that cytotoxic 5FU impairs muscle damage repair and remodeling concomitant with a loss of immune cells that persists beyond the cessation of treatment.NEW & NOTEWORTHY We examined the common chemotherapeutic 5-fluorouracil's (5FU) impact on skeletal muscle immune cells and skeletal muscle repair. 5FU monotherapy decreased body weight and muscle mass, and perturbed skeletal muscle immune cells. In addition, 5FU decreased skeletal muscle immune cells and impaired infiltration following damage contributing to disrupted muscle repair. Our results demonstrate 5FU's impact on skeletal muscle and provide a potential explanation for why some patients may be unable to properly repair damaged tissue.
Subject(s)
Fluorouracil , Monocytes , Animals , Fluorouracil/adverse effects , Macrophages , Mice , Mice, Inbred C57BL , Muscle, Skeletal/physiologyABSTRACT
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.
Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Cachexia/etiology , Dihydrouracil Dehydrogenase (NADP) , Fluorouracil/adverse effects , Mice , Obesity , Quality of LifeABSTRACT
PURPOSE OF REVIEW: Mucositis of the gastrointestinal tract is a debilitating side effect of chemotherapy that negatively influences treatment tolerance and patient life quality. This review will evaluate the recent literature on nonpharmacological strategies that have the potential to improve chemotherapy-induced mucositis (CIM). RECENT FINDINGS: Alternatives to pharmacological approaches have shown great promise in preventing CIM. Natural products, including curcumin, ginseng, quercetin, and patchouli all show potential in mitigating CIM. In addition, dietary patterns, such as the elemental diet, high fiber diet, and diets high in amino acids have documented benefits in preventing CIM. Perhaps the greatest advancement coming to this arena in recent years is in the field of probiotics. Indeed, research on single species as well as probiotic mixtures show potential in reducing CIM insofar as probiotics are now being suggested for treatment of CIM by governing bodies. Although behavioral interventions including psychological interventions and exercise interventions have shown promise in reducing cancer therapy-related side effects, more work in this domain is warranted and particularly in the context of CIM. SUMMARY: Alternatives to pharmacological approaches show great potential for use in prevention and treatment of CIM and should be further developed for use in the clinic.
Subject(s)
Complementary Therapies , Mucositis , Probiotics , Humans , Mucositis/chemically induced , Probiotics/therapeutic useABSTRACT
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.