The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma

Almeida, Luciana Yamamoto; Mariano, Flávia S.; Bastos, Débora Campanella; Cavassani, Karen A.; Raphelson, Janna; Mariano, Vânia Sammartino; Agostini, Michelle; Moreira, Fernanda Santos; Coletta, Ricardo D.; Mattos-Graner, Renata O.; Graner, Edgard

doi:10.1007/s00280-019-04010-1

Cited by 11 publications

(12 citation statements)

References 49 publications

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“…Almeida et al constructed mouse models of spontaneous melanoma metastasis. They reported that orlistat attenuated metastatic capability of melanoma cell lines and activated immune response [ 26 ]. Our findings proved that orlistat treatment reduced lipid metabolism in GC cells.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

et al. 2021

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Background Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Methods Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. Results Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. Conclusions Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.

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Section: Discussionmentioning

confidence: 99%

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

et al. 2021

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“…Orlistat is a tetrahydrolipstatin ( Figure 6) which is an FDA approved gastric and pancreatic lipase inhibitor that works in the intestine by hindering fat absorption by up to 30%, It is used mainly as a weight loss medication in obese patients [158]. Several studies investigated the effect of Orlistat as an antitumorigenic drug in various cancers such as T-cell Leukemia [158], melanoma [159], colorectal cancer [160,161], prostate cancer [162], hepatoma [163], breast cancer, and pancreatic cancer [164]. Orlistat suppresses tumor growth by inhibiting Fatty Acid Synthase (FASN), an anabolic multifunctional enzyme responsible for endogenous fatty acid synthesis from precursors acetyl-CoA and malonyl-CoA to make the 16 carbon polyunsaturated fatty acid palmitate [165,166].…”

Section: Orlistatmentioning

confidence: 99%

“…It is a homodimer comprised of seven catalytic sites per polypeptide chain that act in a successive manner to produce palmitate. Fatty acids are essential for both tumorous and nontumorous cells as they play an essential role in energy storage and in signal transduction [159]. Thus, FASN is crucial for tumor cell survival, making it a desirable target for cancer therapeutics [158,165].…”

Section: Orlistatmentioning

confidence: 99%

“…Finally, a study by Saleh et al indicated that Orlistat exerted a cytotoxic effect and induced apoptosis in human breast cancer (MCF-7) and human pancreatic cancer (PANC-1) cell lines [164]. decreased the cellular proliferation, and size of cancer xenografts in mice, and size and number of cervical and mediastinal lymph nodes, respectively, but also exerted an effect on the fatty acid composition of mitochondrial membranes, which were altered and served to upregulate apoptosis [159]. A study of the effect of Orlistat and NanoOrl, a nanoparticle formulation of Orlistat, on LNCaP and PC3 prostate, and on MDA-MB-231 breast cancer cell lines, showed that both formulations inhibited the thioesterase domain of FASN, and, therefore, lipid synthesis.…”

Section: Orlistatmentioning

confidence: 99%

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Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Ghoneum

Abdulfattah

Warren

et al. 2020

IJMS

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Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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“…Previous studies reported that several immune pathways were associated with the pro-tumorigenic phenotypes of immune cells and protection of tumor cells from the immune attack, ultimately favoring the development and metastasis of tumors (de Almeida et al, 2020;Tsukioki et al, 2020). The distributions of immune cells related to ADARB1 expression are shown in the bubble diagram (Figure 5A) by ssGSEA analysis of Xiantao Tool (https://www.xiantao.love/products).…”

Section: Regulation Of Immune Molecules By Adarb1mentioning

confidence: 99%

Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

et al. 2022

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Chemoresistance, especially temozolomide (TMZ) resistance, is a major clinical challenge in the treatment of glioblastoma (GBM). Exploring the mechanisms of TMZ resistance could help us identify effective therapies. Adenosine deaminases acting on RNA (ADARs) are very important in RNA modification through regulating the A-to-I RNA editing. Recent studies have shown that ADARs regulate multiple neurotransmitter receptors, which have been linked with the occurrence and progress of GBM. Here, data from several bioinformatics databases demonstrated that adenosine deaminase RNA specific B1 (ADARB1), also named ADAR2, was upregulated in both GBM tissues and cells, and had the prognostic value in GBM patients. Moreover, ADARB1 was found to be involved in AKT-mediated TMZ resistance in GBM cells. The KEGG analysis of ADARB1-associated co-expressed genes showed that ADARB1 was potentially involved in the mitochondrial respiratory chain complex. TISIDB and GEPIA databases were further used to analyze the role of ADARB1 in tumor-immune system interactions in GBM. These findings deepened our understanding of the function of ADARB1 in tumorigenesis and therapeutic response in GBM.

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The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma

Cited by 11 publications

References 49 publications

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

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