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

Abstract

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.

SLC39A1 contribute to malignant progression and have clinical prognostic impact in gliomas

“…Zinc is one of the essential trace elements for the human body, and plays an important role in its biological processes, but high concentrations are toxic [23]. It is also a key component of many important enzymes, such as matrix metalloproteinase (MMP) and carbonic anhydrase [24], which are related to tumor proliferation and metastasis [25][26][27][28]. Studies have shown that MMP2\MMP9 are zinc-dependent proteolytic enzymes involved in the remodeling and degradation of extracellular matrix (ECM) and can enhance the invasion and metastasis of glioma [29][30][31].…”

The Crosstalk between Prostate Cancer and Microbiota Inflammation: Nutraceutical Products Are Useful to Balance This Interplay?

“…Carnitine, and in particular its acetylated derivative, Acetyl-l-Carnitine (ALCAR) is involved in mitochondrial membrane trafficking in catabolic and anabolic pathways. Several studies have documented the antioxidant and scavenger activity of this compound, utilized in clinical settings related to disorders where the oxidative stress acts as a promoting factor (e.g., diabetes, Alzheimer's disease, and other neurometabolic disorders) [121,122]. ALCAR reduces PCa cell viability and induces apoptosis; moreover, ALCAR impairs the adhesion, invasion and migration of PC3, DU145, LNCaP, and BPH cells, eliciting a decreasing effect on TNF-α and other proinflammatory cytokines, such as IL-6, CCL2 and CXCL12 [123].…”

SLC39A1 Contribute to Malignant Progression and Have Clinical Prognostic Impact in Gliomas

“…Zinc is one of the essential trace elements for the human body, and plays an important role in its biological processes, but high concentrations are toxic [23]. It is also a key component of many important enzymes, such as matrix metalloproteinase (MMP) and carbonic anhydrase [24], which are related to tumor proliferation and metastasis [25][26][27][28]. Studies have shown that MMP2\MMP9 participates in the degradation of extracellular matrix, destroys the basilar membrane, and provides conditions for tumor invasion and metastasis [29,30].…”