&lt;smlcap&gt;L&lt;/smlcap&gt;-Carnitine Ameliorates Cancer Cachexia in Mice Partly via the Carnitine Palmitoyltransferase-Associated PPAR-&amp;#947; Signaling Pathway

Jiang, Fuming; Zhang, Zongqi; Zhang, Yi; Pan, Xiaohui; Yu, Ling; Liu, Su

doi:10.1159/000439550

Cited by 29 publications

(20 citation statements)

References 29 publications

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“…1e). The selected ALCAR concentrations are in line with our previously results on endothelial cells, and other preclinical and clinical studies [17, 20, 24, 30, 36]. The effect of ALCAR on cell growth was in part due to induction of apoptosis, as determined by flow cytometry.…”

Section: Resultssupporting

confidence: 82%

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Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

Baci

Bruno

Cascini

et al. 2019

J Exp Clin Cancer Res

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BackgroundProstate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR.MethodsThe chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts.ResultsWe found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo.ConclusionsOur results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible “repurposed agent’ for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

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Section: Resultssupporting

confidence: 82%

“…Carnitine has been reported as highly efficient in the downregulation of pro-inflammatory cytokines TNF-α and IL-6 in murine models of cancer cachexia [24, 36], liver fibrosis [23] and in blocking TNF-α-induced insulin resistance in skeletal muscle cells [48].…”

Section: Discussionmentioning

confidence: 99%

Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

Baci

Bruno

Cascini

et al. 2019

J Exp Clin Cancer Res

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“…PPARb/d is the least well-characterized of the PPARs, but it is ubiquitously expressed in most tissues, regulates blood cholesterol and glucose levels, and is involved in fatty acid oxidation (43). Because PPARs play an obvious role in regulating whole body energy homeostasis, there has been significant success in modulating these transcription factors for the benefit of patients with diabetes, dyslipidemia, and atherosclerosis (44); and promising anticatabolic efficacy has been observed with PPAR agonists in mouse models of Lewis lung carcinoma (45), colon adenocarcinoma (46), and non-small-cell lung cancer (47). PPARg is 1 of the main regulators of adipocyte differentiation (48,49) and is downregulated in SkM of patients with breast cancer (23) and BC-PDOX-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator–activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue

Wilson

Rhodes

Rodríguez

et al. 2019

Clinical Cancer Research

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Purpose: This study tested the hypothesis that a patientderived orthotopic xenograft (PDOX) model would recapitulate the common clinical phenomenon of breast cancer-induced skeletal muscle (SkM) fatigue in the absence of muscle wasting. This study additionally sought to identify drivers of this condition to facilitate the development of therapeutic agents for patients with breast cancer experiencing muscle fatigue. Experimental Design: Eight female BC-PDOX-bearing mice were produced via transplantation of tumor tissue from 8 female patients with breast cancer. Individual hind limb muscles from BC-PDOX mice were isolated at euthanasia for RNA-sequencing, gene and protein analyses, and an ex vivo muscle contraction protocol to quantify tumor-induced aberrations in SkM function. Differentially expressed genes (DEG) in the BC-PDOX mice relative to control mice were identified using DESeq2, and multiple bioinformatics platforms were employed to contextualize the DEGs. Results: We found that SkM from BC-PDOX-bearing mice showed greater fatigability than control mice, despite no differences in absolute muscle mass. PPAR, mTOR, IL6, IL1, and several other signaling pathways were implicated in the transcriptional changes observed in the BC-PDOX SkM. Moreover, 3 independent in silico analyses identified PPAR signaling as highly dysregulated in the SkM of both BC-PDOX-bearing mice and human patients with early-stage nonmetastatic breast cancer. Conclusions: Collectively, these data demonstrate that the BC-PDOX model recapitulates the expected breast cancer-induced SkM fatigue and further identify aberrant PPAR signaling as an integral factor in the pathology of this condition.

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“…To this end, multiple lines of research have suggested that a combination treatment of butyrate and carnitine/acetylcarnitine can exert greater effects on cancerous cells than butyrate treatment alone, possibly by enhancing butyrate localization to the mitochondria [ 99 , 100 ]. Oral l -carnitine supplementation also mitigated cancer cachexia symptoms in BALB/c mice injected with adenocarcinoma cells [ 101 , 102 ].…”

Section: Butyrate In the Gastrointestinal Tractmentioning

confidence: 99%

Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance

2017

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Increased dietary fiber consumption has been associated with many beneficial effects, including amelioration of obesity and insulin resistance. These effects may be due to the increased production of short chain fatty acids, including propionate, acetate and butyrate, during fermentation of the dietary fiber in the colon. Indeed, oral and dietary supplementation of butyrate alone has been shown to prevent high fat-diet induced obesity and insulin resistance. This review focuses on sources of short chain fatty acids, with emphasis on sources of butyrate, mechanisms of fiber and butyrate metabolism in the gut and its protective effects on colon cancer and the peripheral effects of butyrate supplementation in peripheral tissues in the prevention and reversal of obesity and insulin resistance.

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<smlcap>L</smlcap>-Carnitine Ameliorates Cancer Cachexia in Mice Partly via the Carnitine Palmitoyltransferase-Associated PPAR-γ Signaling Pathway

Cited by 29 publications

References 29 publications

Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies

Human Breast Cancer Xenograft Model Implicates Peroxisome Proliferator–activated Receptor Signaling as Driver of Cancer-induced Muscle Fatigue

Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance

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