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1.
J Cell Physiol ; 235(1): 526-537, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241186

RESUMO

Muscle wasting is associated with chronic diseases and cancer. Elucidation of the biological mechanism involved in the process of muscle mass loss and cachexia may help identify therapeutic targets. We hypothesized that l-carnitine treatment may differentially revert muscle fiber atrophy and other structural alterations in slow- and fast-twitch limb muscles of rats bearing the Yoshida ascites hepatoma. In soleus and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with l-carnitine (1 g/kg body weight for 7 days, intragastric), food intake, body and muscle weights, fiber typing and morphometry, morphological features, redox balance, autophagy and proteolytic, and signaling markers were explored. Levels of carnitine palmitoyl transferase were also measured in all the study muscles. l-Carnitine treatment ameliorated the atrophy of both slow- and fast-twitch fibers (gastrocnemius particularly), muscle structural alterations (both muscles), and attenuated oxidative stress, proteolytic and signaling markers (gastrocnemius). Despite that carnitine palmitoyl transferase-1 levels increased in both muscle types in a similar fashion, l-carnitine ameliorated muscle atrophy and proteolysis in a muscle-specific manner in cancer-induced cachexia. These data reveal the need to study muscles of different fiber type composition and function to better understand whereby l-carnitine exerts its beneficial effects on the myofibers in muscle wasting processes. These findings also have potential clinical implications, since combinations of various exercise and muscle training modalities with l-carnitine should be specifically targeted for the muscle groups to be trained.


Assuntos
Caquexia/tratamento farmacológico , Carnitina/farmacologia , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Lenta/patologia , Atrofia Muscular/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Caquexia/patologia , Carcinoma Hepatocelular/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Músculo Esquelético/fisiologia , Atrofia Muscular/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ratos , Ratos Wistar , Sarcoma de Yoshida/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Curr Opin Oncol ; 31(4): 286-290, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30893144

RESUMO

PURPOSE OF REVIEW: The aim of this article is to review the metabolic background of the cachectic syndrome and to analyze the recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. RECENT FINDINGS: The main changes associated with the development of this multiorganic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. Among the most promising approaches for the treatment of cachexia include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and antimyostatin peptides. The multitargeted 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 aspect for 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 weight loss can be detected. SUMMARY: Cancer cachexia has two main components: anorexia and metabolic alterations and both have to be taken into consideration for the treatment of the syndrome.


Assuntos
Caquexia/metabolismo , Caquexia/terapia , Neoplasias/metabolismo , Neoplasias/terapia , Caquexia/patologia , Exercício Físico , Humanos , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Neoplasias/patologia
3.
Semin Cell Dev Biol ; 54: 20-7, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26343953

RESUMO

Cancer cachexia is a frequent syndrome that dramatically affects patient quality of life, anti-cancer treatment effectiveness, and overall survival. To date, no effective treatment is available and most of the studies are performed in experimental models in order to uncover the underlying mechanisms and to design prospective therapeutic strategies. This review summarizes the most relevant information regarding the use of animal models for studying cancer cachexia. Technical limitations and degree of recapitulation of the features of human cachexia are highlighted, in order to help investigators choose the most suitable model according to study-specific endpoints.


Assuntos
Caquexia/etiologia , Neoplasias/complicações , Animais , Caquexia/patologia , Modelos Animais de Doenças , Engenharia Genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
4.
Biochem J ; 474(16): 2663-2678, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28751550

RESUMO

Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, ß-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.


Assuntos
Caquexia/terapia , Neoplasias/terapia , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Anorexia/metabolismo , Anorexia/patologia , Anorexia/terapia , Caquexia/metabolismo , Caquexia/patologia , Dietoterapia/métodos , Terapia por Exercício/métodos , Grelina/agonistas , Humanos , Miostatina/antagonistas & inibidores , Miostatina/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/uso terapêutico
5.
Int J Cancer ; 138(8): 2021-9, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26595367

RESUMO

Formoterol is a highly potent ß2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the ß2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.


Assuntos
Receptores de Activinas Tipo II/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Caquexia/prevenção & controle , Carcinoma Pulmonar de Lewis/complicações , Fumarato de Formoterol/farmacologia , Animais , Caquexia/patologia , Carcinoma Pulmonar de Lewis/patologia , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
Curr Opin Clin Nutr Metab Care ; 18(3): 221-5, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25769061

RESUMO

PURPOSE OF REVIEW: The aim of the present review is to examine the impact of mitochondrial dysfunction in cancer cachexia. RECENT FINDINGS: Oxidative pathways are altered in this tissue during muscle wasting and this seems to be a consequence of mitochondrial abnormalities that include altered morphology and function, decreased ATP synthesis and uncoupling. SUMMARY: An alteration of energy balance is the immediate cause of cachexia. Both alterations in energy intake and expenditure are responsible for the wasting syndrome associated with different types of pathological conditions, such as cancer. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss, one of which is mitochondrial dysfunction.


Assuntos
Caquexia/fisiopatologia , Metabolismo Energético , Mitocôndrias/fisiologia , Músculo Esquelético/fisiologia , Atrofia Muscular/fisiopatologia , Neoplasias/complicações , Síndrome de Emaciação/fisiopatologia , Trifosfato de Adenosina/metabolismo , Caquexia/etiologia , Caquexia/metabolismo , Humanos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/metabolismo , Redução de Peso
7.
Mediators Inflamm ; 2015: 182872, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26523094

RESUMO

Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia.


Assuntos
Caquexia/patologia , Neoplasias/patologia , Tecido Adiposo/patologia , Animais , Peso Corporal , Encéfalo/patologia , Caquexia/complicações , Humanos , Intestinos/patologia , Fígado/patologia , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Músculos/fisiopatologia , Miocárdio/patologia , Neoplasias/complicações , Distribuição Tecidual
8.
Biochim Biophys Acta ; 1830(3): 2770-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23200745

RESUMO

BACKGROUND: Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass. METHODS: The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques. RESULTS: Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei. Analyzing the expression of some factors related to proteolytic and thermogenic processes, we observed in tumor-bearing animals an increased expression of genes involved in proteolysis such as ubiquitin ligases Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box protein (MAFBx). Moreover, an overexpression of both sarco/endoplasmic Ca(2+)-ATPase (SERCA1) and adenine nucleotide translocator (ANT1), both factors related to cellular energetic efficiency, was observed. Tumor burden also leads to a marked decreased in muscle ATP content. CONCLUSIONS: In addition to muscle proteolysis, other ATP-related pathways may have a key role in muscle wasting, both directly by increasing energetic inefficiency, and indirectly, by affecting the sarcoplasmic reticulum-mitochondrial assembly that is essential for muscle function and homeostasis. GENERAL SIGNIFICANCE: The present study reports profound morphological changes in cancer cachectic muscle, which are visualized mainly in alterations in sarcoplasmic reticulum and mitochondria. These alterations are linked to pathways that can account for energy inefficiency associated with cancer cachexia.


Assuntos
Caquexia/metabolismo , Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Sarcoma de Yoshida/metabolismo , Retículo Sarcoplasmático/metabolismo , Translocador 1 do Nucleotídeo Adenina/genética , Translocador 1 do Nucleotídeo Adenina/metabolismo , Trifosfato de Adenosina/deficiência , Animais , Apoptose/genética , Caquexia/complicações , Caquexia/patologia , Núcleo Celular/ultraestrutura , Metabolismo Energético/genética , Expressão Gênica , Masculino , Mitocôndrias/ultraestrutura , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/complicações , Atrofia Muscular/patologia , Proteólise , Ratos , Ratos Wistar , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Sarcoma de Yoshida/complicações , Sarcoma de Yoshida/patologia , Retículo Sarcoplasmático/ultraestrutura , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
9.
Gastroenterology ; 144(3): 636-649.e6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23142626

RESUMO

BACKGROUND & AIMS: Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean, and do not develop hepatosteatosis when fed a high-fat diet. Herein, we sought to investigate the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism. METHODS: Chronic central administration of MCH and adenoviral vectors increasing MCH signaling were performed in rats and mice. Vagal denervation was performed to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time polymerase chain reaction and Western blot. RESULTS: We showed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-Jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism. CONCLUSIONS: Our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adiposidade/fisiologia , Região Hipotalâmica Lateral/fisiologia , Hormônios Hipotalâmicos/fisiologia , Fígado/metabolismo , Melaninas/fisiologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Hormônios Hipofisários/fisiologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Ingestão de Alimentos , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Região Hipotalâmica Lateral/efeitos dos fármacos , Hormônios Hipotalâmicos/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Lipogênese/efeitos dos fármacos , Lipogênese/fisiologia , Fígado/efeitos dos fármacos , Masculino , Melaninas/administração & dosagem , Camundongos , Hepatopatia Gordurosa não Alcoólica , Hormônios Hipofisários/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores do Hormônio Hipofisário/agonistas , Receptores do Hormônio Hipofisário/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia , Nervo Vago/fisiopatologia
10.
Muscle Nerve ; 49(2): 233-48, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23649607

RESUMO

INTRODUCTION: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. METHODS: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals with cachexia and control animals. CONCLUSIONS: The differences observed pertain to genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome.


Assuntos
Carcinoma Hepatocelular/fisiopatologia , Acoplamento Excitação-Contração/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Hepáticas/fisiopatologia , Músculo Esquelético/fisiopatologia , Animais , Caquexia/etiologia , Caquexia/genética , Caquexia/fisiopatologia , Cálcio/metabolismo , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Acoplamento Excitação-Contração/genética , Homeostase/fisiologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Masculino , Ratos , Ratos Wistar
11.
Physiol Rep ; 12(18): e70044, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39294861

RESUMO

Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH-130 ascites hepatoma model of cancer cachexia. AH-130 tumor-bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage-inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon-γ in the heart, while an increase in interleukin-1ß mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH-130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro-inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting.


Assuntos
Caquexia , Músculo Esquelético , Miocárdio , Resposta a Proteínas não Dobradas , Animais , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/patologia , Caquexia/genética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Ratos , Miocárdio/metabolismo , Miocárdio/patologia , Ratos Wistar , Estresse do Retículo Endoplasmático , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genética
12.
J Lipid Res ; 54(11): 3045-51, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23966665

RESUMO

Cancer-associated cachexia is characterized, among other symptoms, by a dramatic loss of both muscle and fat. In addition, the cachectic syndrome is often associated with anemia. The object of the present investigation was to assess the effects of erythropoietin (EPO) treatment on experimental cancer cachexia models. The results clearly show that, in addition to the improvement of the hematocrit, EPO treatment promoted a partial preservation of adipose tissue while exerting negligible effects on muscle loss. Administration of EPO to tumor-bearing animals resulted in a significant increase of lipoprotein lipase (LPL) activity in adipose tissue, suggesting that the treatment favored triacylglycerol (TAG) accumulation in the adipose tissue. In vitro experiments using both adipose tissue slices and 3T3-L1 adipocytes suggests that EPO is able to increase the lipogenic rate through the activation of its specific receptor (EPOR). This metabolic pathway, in addition to TAG uptake by LPL, may contribute to the beneficial effects of EPO on fat preservation in cancer cachexia.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Caquexia/complicações , Caquexia/patologia , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Neoplasias/complicações , Células 3T3-L1 , Animais , Caquexia/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Ratos , Receptores da Eritropoetina/metabolismo
13.
Nat Rev Clin Oncol ; 20(4): 250-264, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36806788

RESUMO

Cachexia is a devastating, multifactorial and often irreversible systemic syndrome characterized by substantial weight loss (mainly of skeletal muscle and adipose tissue) that occurs in around 50-80% of patients with cancer. Although this condition mainly affects skeletal muscle (which accounts for approximately 40% of total body weight), cachexia is a multi-organ syndrome that also involves white and brown adipose tissue, and organs including the bones, brain, liver, gut and heart. Notably, cachexia accounts for up to 20% of cancer-related deaths. Cancer-associated cachexia is invariably associated with systemic inflammation, anorexia and increased energy expenditure. Understanding these mechanisms is essential, and the progress achieved in this area over the past decade could help to develop new therapeutic approaches. In this Review, we examine the currently available evidence on the roles of both the tumour macroenvironment and microenvironment in cancer-associated cachexia, and provide an overview of the novel therapeutic strategies developed to manage this syndrome.


Assuntos
Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Neoplasias/complicações , Neoplasias/patologia , Tecido Adiposo/patologia , Músculo Esquelético/patologia , Anorexia/complicações , Anorexia/patologia , Microambiente Tumoral
14.
Cancers (Basel) ; 15(4)2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36831431

RESUMO

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

15.
J Cachexia Sarcopenia Muscle ; 14(3): 1244-1248, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37130578

RESUMO

BACKGROUND: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. METHODS: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). RESULTS: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). CONCLUSIONS: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.


Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Camundongos , Animais , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Músculo Esquelético/patologia , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/patologia , Pâncreas/patologia
16.
Front Oncol ; 13: 1237709, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38234397

RESUMO

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a ß2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

17.
J Cachexia Sarcopenia Muscle ; 14(1): 653-660, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36346141

RESUMO

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.


Assuntos
Caquexia , Neoplasias Hepáticas , Camundongos , Ratos , Humanos , Animais , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/metabolismo , Oxprenolol/uso terapêutico , Ratos Wistar , Qualidade de Vida , Ratos Endogâmicos Lew , Antagonistas Adrenérgicos beta/uso terapêutico , Pindolol
18.
Sci Rep ; 12(1): 16704, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202959

RESUMO

Wastewater-based epidemiology has shown to be an efficient tool to track the circulation of SARS-CoV-2 in communities assisted by wastewater treatment plants (WWTPs). The challenge comes when this approach is employed to help Health authorities in their decision-making. Here, we describe the roadmap for the design and deployment of SARSAIGUA, the Catalan Surveillance Network of SARS-CoV-2 in Sewage. The network monitors, weekly or biweekly, 56 WWTPs evenly distributed across the territory and serving 6 M inhabitants (80% of the Catalan population). Each week, samples from 45 WWTPs are collected, analyzed, results reported to Health authorities, and finally published within less than 72 h in an online dashboard ( https://sarsaigua.icra.cat ). After 20 months of monitoring (July 20-March 22), the standardized viral load (gene copies/day) in all the WWTPs monitored fairly matched the cumulative number of COVID-19 cases along the successive pandemic waves, showing a good fit with the diagnosed cases in the served municipalities (Spearman Rho = 0.69). Here we describe the roadmap of the design and deployment of SARSAIGUA while providing several open-access tools for the management and visualization of the surveillance data.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Humanos , Pandemias , RNA Viral , Esgotos , Águas Residuárias , Vigilância Epidemiológica Baseada em Águas Residuárias
19.
Muscle Nerve ; 43(2): 268-73, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21254094

RESUMO

Proteolysis in skeletal muscle is mainly carried out by the activity of the ubiquitin-dependent proteolytic system. For the study of protein degradation through the ubiquitin-proteasome pathway, we used a model of hyperthermia in murine myotubes. In C2C12 cells, hyperthermia (41°C) induced a significant increase in both the rate of protein synthesis (18%) and degradation (51%). Interestingly, the addition of the ß(2) -adrenoceptor agonist formoterol resulted in a significant decrease in protein degradation (21%) without affecting protein synthesis. The decrease in proteolytic rate was associated with decreases in gene expression of the different components of the ubiquitin-dependent proteolytic system. The effects of the ß(2) -agonist on protein degradation were dependent exclusively on cAMP formation, because inhibition of adenylyl cyclase completely abolished the effects of formoterol on protein degradation. It can be concluded that hyperthermia is a suitable model for studying the anti-proteolytic potential of drugs used in the treatment of muscle wasting.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Etanolaminas/farmacologia , Hipertermia Induzida , Fibras Musculares Esqueléticas/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinas/metabolismo , Análise de Variância , Animais , Linhagem Celular Transformada , AMP Cíclico/metabolismo , DDT/análogos & derivados , DDT/farmacologia , Fumarato de Formoterol , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Imunossupressores/farmacologia , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Camundongos , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Miofibrilas/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Ubiquitinas/genética
20.
Onco Targets Ther ; 14: 1953-1959, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33762827

RESUMO

BACKGROUND: During cancer cachexia, both skeletal muscle and adipose tissue losses take place. The use of ß2-agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in pre-clinical models. The object of the present research was to study the effects of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1), on body weight loss and cachexia in tumour-bearing animals. METHODS: Rats were separated into two groups: controls (C) and tumour bearing (TB). TB group was further subdivided into four groups: untreated (saline as a vehicle), treated with Formoterol (TF) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with Dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and Dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). 7 days after tumour transplantation, muscle weight, grip force, and total physical activity were specified in all experimental groups. RESULTS: While formoterol had, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle nor on any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the ß2-agonist. CONCLUSION: It is concluded that, in the preclinical cachectic model used, no synergy exists between ß2-agonist treatment and the blockade of sarcoplasmic-calcium flow.

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