Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice

Fermoselle, Clara; Garcı́a-Arumı́, Elena; Puig-Vilanova, Ester; Andreu, Antoni L.; Urtreger, Alejandro J.; Joffé, Elisa D. Bal de Kier; Tejedor, Alberto; Puente-Maestu, Luís; Barreiro, Esther

doi:10.1113/expphysiol.2013.072496

Cited by 56 publications

(95 citation statements)

References 57 publications

(124 reference statements)

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“…The experimental model used in the present study has been well-validated in previous investigations [20][21][22][23][24][25] and has enabled us the analysis of markers of tumor growth and degradation in response to several pharmacological agents in mice bearing the LP07 lung adenocarcinoma. Moreover, as a novelty, specific markers of cancer-associated fibroblasts have also been identified such as Snail1 and S100A4 [38,39].…”

Section: Discussionmentioning

confidence: 90%

“…LP07 cell line shares identical characteristics with the P07 tumor regarding both lung tumor incidence and histology [20][21][22]. Moreover, one month after tumor transplantation, all animals developed lung metastasis and spleen enlargement without affecting other organs [20][21][22][23]25]. …”

Section: Animal Experimentsmentioning

confidence: 94%

“…The positron emission tomography (PET) was conducted in the LC group on days 13 and 20 in order to verify the tumor progression, as shown in previous studies [23,25]. Tumor sizes were extracted and weighed out on day 30 right after the sacrifice of the animals ( Figure E1).…”

Section: In Vivo Measurements In the Micementioning

confidence: 99%

“…In the tumor specimens from all groups, inflammatory and vascular markers were identified on the three-micrometer tumor paraffin-embedded sections using immunohistochemical procedures as previously described in our group [23,25]. In these experiments the following antibodies were used: COX-2 (anti-COX-2 antibody, Santa Cruz), NF-κB (p65) (anti-NF-κB (p65), Santa Cruz), ki-67 (anti-ki67 antibody, Millipore Iberica, CA, USA), Bax (anti-Bax antibody, Santa Cruz), fibulin-5 (anti-fib-5 antibody, Santa Cruz),…”

Section: Tumor Biology Analysesmentioning

confidence: 99%

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Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology

Mateu-Jiménez¹,

Fermoselle²,

Rojo³

et al. 2016

CPD

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Lung cancer (LC) remains the leading cause of cancer mortality worldwide, and non-small cell LC (NSCLC) represents 80% of all LC. Oxidative stress and inflammation, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen activated protein kinases (MAPK) participate in LC pathophysiology. Currently available treatment for LC is limited and in vivo models are lacking. We hypothesized that antioxidants and NF-κB, MAPK, and proteasome inhibitors may exert an antitumoral response through attenuation of several key biological mechanisms that promote tumorigenesis and cancer cell growth. Body and tumor weights, oxidative stress, antioxidants, inflammation, NF-κB p65 expression, fibulins, apoptosis, autophagy, tumor and stroma histology were evaluated in the subcutaneous tumor of LC (LP07 adenocarcinoma) BALB/c mice, with and without concomitant treatment with NF-κB (sulfasalazine), MEK (U0126), and proteasome (bortezomib) inhibitors, and N-acetyl cysteine (NAC). Compared to LC control mice, in subcutanous tumors, the four pharmacological agents reduced oxidative stress markers and tumor proliferation (ki-67).Inflammation and NF-κB p65 expression were attenuated by NF-κB and MAPK inhibitors, and the latter also enhanced apoptotic markers. Catalase was induced by the three inhibitors, while bortezomib also promoted superoxide dismutase expression. NF-κB and MEK inhibitors significantly reduced tumor burden through several biological mechanisms that favored tumor degradation and attenuated tumor proliferation. These two pharmacological agents may enhance the anti-tumor activity of selectively targeted therapeutic strategies for LC. Proteasomal inhibition using bortezomib rather promotes tumor degradation, while treatment with antioxidants cannot be recommended. This experimental model supports the use of adjuvant drugs for the improvement of LC treatment.Word count: 250

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Section: Discussionmentioning

confidence: 90%

Section: Animal Experimentsmentioning

confidence: 94%

Section: In Vivo Measurements In the Micementioning

confidence: 99%

Section: Tumor Biology Analysesmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology

Mateu-Jiménez¹,

Fermoselle²,

Rojo³

et al. 2016

CPD

Self Cite

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“…Skeletal muscles from cachectic tumor-bearing mice had reduced ATP synthesis rates and increased mitochondrial uncoupling (113), as well as NF-B-and mitogen-activated protein kinase-dependent mitochondrial dysfunction (40). Furthermore, both skeletal muscles and hearts from Yoshida AH-130 tumorbearing rats exhibited increased oxidation of proteins involved in glycolysis, ATP production and distribution, muscle contraction, and mitochondrial function (69).…”

Section: Pathogenesis Of Cardiac Atrophy In Cancer Cachexia: Proteinmentioning

confidence: 99%

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

Murphy

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia.

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Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure

et al. 2015

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Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N-acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline-induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF-cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non-cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin-proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF-κB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF-cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin-1, MURF-1, NF-κB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow- and fast-twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF-cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF-κB transcriptional activity in both muscles. Treatment of CHF-cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF-cachectic patients.

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Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice

Cited by 56 publications

References 57 publications

Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology

Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure

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