Pharmacological Strategies in Lung Cancer-Induced Cachexia: Effects on Muscle Proteolysis, Autophagy, Structure, and Weakness

Chacon-Cabrera, Alba; Fermoselle, Clara; Urtreger, Alejandro J.; Mateu-Jiménez, Mercè; Diament, Miriam J.; Joffé, Elisa D. Bal de Kier; Sandri, Marco; Barreiro, Esther

doi:10.1002/jcp.24611

Cited by 79 publications

(226 citation statements)

References 62 publications

(114 reference statements)

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“…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%

“…Thus, key biological events such as cell proliferation, redox balance, inflammation, apoptosis, and autophagy were analyzed in the subcutaneous tumors of lung adenocarcinoma cells in BALB/c mice in response to several pharmacological agents that directly influence tumor growth and survival, namely the antioxidant N-acetyl cysteine (NAC), and the inhibitors of MAPK (MEK), NF-κB, and proteasome pathways: U0126, sulfasalazine, and bortezomib, respectively. The current model has been previously validated [20][21][22][23][24], and is the only approach to obtain sufficient material to warrant the reliability of the biological determinations in the tumors, since they would have not been possibly analyzed in the lung micrometastasis of the experimental mice.…”

Section: Introductionmentioning

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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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: Animal Experimentsmentioning

confidence: 94%

Section: In Vivo Measurements In the Micementioning

confidence: 99%

Section: Introductionmentioning

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

Self Cite

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“…Protein levels of the different molecular markers in lung specimens were explored using methodologies previously published (23,32,33). The following antibodies were used to detect the different molecular markers: total protein carbonylation (OxyBlot Protein Oxidation Detection Kit, Chemicon International Inc.), malondialdehyde protein adducts ( anti-MDA-protein adducts antibody, Academy Bio-Medical Company Inc.), total protein nitration patients compared with nontumor specimens of LC patients (Figures 2A, B).…”

Section: Molecular Biology Analysesmentioning

confidence: 99%

Redox Imbalance in Lung Cancer of Patients with Underlying Chronic Respiratory Conditions

Mateu-Jiménez

Sánchez-Font

Rodríguez-Fuster

et al. 2016

Mol Med

Self Cite

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Chronic respiratory diseases such as obstructive pulmonary disease (COPD) and oxidative stress may underlie lung cancer (LC). We hypothesized that the profile of oxidative and antioxidant events may differ in lung tumors and blood compartments of patients with non-small cell LC (NSCLC) with and without COPD. Redox markers (immunoblotting, ELISA, chemiluminescence, 2D electrophoresis and proteomics) were analyzed in blood samples of 17 control subjects and 80 LC patients (59 LC-COPD and 21 LC) and lung specimens (tumor and nontumor) from those undergoing thoracotomy (35 patients: 23 LC-COPD and 12 LC). As smoking history was more prevalent in LC-COPD patients, these were further analyzed post hoc as heavy and moderate smokers (cutoff, 60 pack-years). Malondialdehyde (MDA)-protein adducts and SOD1 levels were higher in tumor and nontumor samples of LC-COPD than in LC. In tumors compared with nontumors, SOD2 protein content was greater, whereas catalase levels were decreased in both LC and LC-COPD patients. Blood superoxide anion levels, protein carbonylation and nitration were greater in LC and LC-COPD patients than in the controls, and in the latter patients compared with the former. Systemic superoxide anion, protein carbonyls and nitrotyrosine above specific cutoff values best identified underlying COPD among all patients. Smoking did not influence the study results. A differential expression profile of oxidative stress markers exists in blood and, to a lesser extent, in the tumors of LC-COPD patients. These findings suggest that systemic oxidative stress and lung antioxidants (potential biomarkers) may predispose patients with chronic respiratory diseases to a higher risk for LC.

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“…This has been shown for proteasome inhibitors such as bortezomib (4) (5) , while suppression of autophagy may even reveal detrimental (6)(7) (8) . The possibility that muscle-specific inhibition of proteolysis might prove effective remains an open question, however.…”

Section: Introductionmentioning

confidence: 87%

Novel investigational drugs mimicking exercise for the treatment of cachexia

Penna

Ballarò

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction: Cachexia is a syndrome characterized by body weight loss, muscle wasting, and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, able to both induce anabolism and inhibit catabolism.Areas covered in this review: This review will focus on exercise mimetics and on their potential inclusion in combined protocols to treat cachexia, with particular reference to the cancer-associated one.Expert opinion: Despite exercise improves muscle phenotype, most patients retain sedentary habits quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and co-morbidities that reduce exercise tolerance. For these reasons drugs mimicking exercise could be beneficial also in the absence of patient compliance to the practice of physical activity. Different exercise mimetics are now available and, yet some of them may exert serious side-effects, investigating their effectiveness on muscle phenotype will provide a new tool for the management of cachexia.4

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Pharmacological Strategies in Lung Cancer-Induced Cachexia: Effects on Muscle Proteolysis, Autophagy, Structure, and Weakness

Cited by 79 publications

References 62 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

Redox Imbalance in Lung Cancer of Patients with Underlying Chronic Respiratory Conditions

Novel investigational drugs mimicking exercise for the treatment of cachexia

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