Orlistat Reduces Proliferation and Enhances Apoptosis in Human Pancreatic Cancer Cells (PANC-1)

Sokołowska, Ewa; Presler, Malgorzata; Goyke, Elżbieta; Milczarek, Ryszard; Świerczyński, Julian; Śledziński, Tomasz

doi:10.21873/anticanres.12083

Cited by 14 publications

(15 citation statements)

References 17 publications

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“…Most importantly, some inhibitors show selective activity against CSCs rather than bulk tumor cells. Strikingly, Orlistat, a FDA-approved anti-obesity drug targeting FASN, exerts a potent anti-tumor activity in various cancers [ 201 , 202 ]. Remarkably, inhibition of FASN by Orlistat in EGFR mutated NSCLC suppresses tumor growth in vitro and in vivo through reducing EGFR palmitoylation but inducing mutant EGFR ubiquitination and subsequent proteasomal degradation [ 203 ].…”

Section: Targeting Lipid Metabolism As Novel Therapeutic Strategies Amentioning

confidence: 99%

Emerging role of lipid metabolism alterations in Cancer stem cells

Man

Chen

et al. 2018

J Exp Clin Cancer Res

178

149

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BackgroundCancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs.Main bodyRecent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism.ConclusionIncreased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.

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Section: Targeting Lipid Metabolism As Novel Therapeutic Strategies Amentioning

confidence: 99%

Emerging role of lipid metabolism alterations in Cancer stem cells

Man

Chen

et al. 2018

J Exp Clin Cancer Res

178

149

View full text Add to dashboard Cite

show abstract

“…Orlistat contains a highly reactive beta-lactone that covalently captures reactive serine residues such as Ser2308 within the TE domain of FASN [ 119 ]. Its anti-tumor properties have been explored extensively where studies have shown shrinkage in tumors both in vitro and in vivo [ 75 , 89 ]. However, Orlistat is highly unstable due to the presence of beta-lactone, has poor water solubility and poor gastrointestinal absorption that hinders its advancement in clinical trials [ 120 ].…”

Section: Targeting Fasn In Cancermentioning

confidence: 99%

Fatty Acid Synthase: An Emerging Target in Cancer

2020

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In recent years, lipid metabolism has garnered significant attention as it provides the necessary building blocks required to sustain tumor growth and serves as an alternative fuel source for ATP generation. Fatty acid synthase (FASN) functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors with lipogenic phenotypes. Accumulating evidence has shown that it is capable of rewiring tumor cells for greater energy flexibility to attain their high energy requirements. This multi-enzyme protein is capable of modulating the function of subcellular organelles for optimal function under different conditions. Apart from lipid metabolism, FASN has functional roles in other cellular processes such as glycolysis and amino acid metabolism. These pivotal roles of FASN in lipid metabolism make it an attractive target in the clinic with several new inhibitors currently being tested in early clinical trials. This article aims to present the current evidence on the emergence of FASN as a target in human malignancies.

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“…TVB-2640 has entered clinical trials, e.g., for people with resectable colon cancer (phase 1), for advanced breast cancer (phase 2), or for high grade astrocytoma (phase 2). Orlistat is a US food and Drug Administration (FDA)-approved anti-obesity drug, and it has been shown that orlistat reduces human pancreatic cancer cell growth [ 14 , 95 ]. As orlistat has low oral bioavailability which may reduce cancer therapy effect [ 7 ], several studies suggest combination therapies with ALCAR (AMPK activator) for prostate cancer [ 96 ], or simultaneous targeting glycolysis, glutaminolysis, and FA synthesis by lonidamine, 6-diazo-5-oxo- l -norleucine which are combined with orlistat for colon cancer therapy [ 97 ].…”

Section: Targeting Lipid Metabolism and Therapy Options For Cancermentioning

confidence: 99%

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Sunami

Rebelo

Kleeff

2017

Cancers

117

109

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Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer.

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Orlistat Reduces Proliferation and Enhances Apoptosis in Human Pancreatic Cancer Cells (PANC-1)

Abstract: This study showed, to our knowledge for the first time, that orlistat exhibits significant antitumor activity against PANC-1 cells. This implies that orlistat analogs with good oral bioavailability may find application in pharmacotherapy of pancreatic cancer.

Cited by 14 publications

References 17 publications

Emerging role of lipid metabolism alterations in Cancer stem cells

Emerging role of lipid metabolism alterations in Cancer stem cells

Fatty Acid Synthase: An Emerging Target in Cancer

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

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