Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy

Schcolnik‐Cabrera, Alejandro; Chávez‐Blanco, Alma; Domínguez-Gómez, Guadalupe; Taja‐Chayeb, Lucía; Morales‐Bárcenas, Rocío; Trejo-Becerril, Catalina; Pérez-Cárdenas, Enrique; González-Fierro, Aurora; Dueñas‐González, Alfonso

doi:10.1080/13543784.2018.1471132

Cited by 101 publications

(75 citation statements)

References 139 publications

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“…Orlistat is able to irreversibly inhibit the thioesterase domain of FASN through the action of a highly reactive beta-lactone group that covalently binds the active site serine residue (Ser 2308) 41 . Studies have additionally shown that the reactive beta-lactone group of orlistat can inhibit the activity of multiple cellular enzymes 42 . Other inhibitors of FASN such as cerulenin and C-75 have similar off target effects 43 .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

Hitakarun

Khongwichit

Wikan

et al. 2020

Sci Rep

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Many mosquito transmitted viruses of the genera Alphavirus and Flavivirus are human pathogens of significant concern, and there is currently no specific antiviral for any member of these two genera. This study sought to investigate the broad utility of orlistat (tetrahydrolipstatin) in reducing virus infection for several mosquito borne viruses including flaviviruses (dengue virus (DENV; nine isolates analyzed), Japanese encephalitis virus (JEV; one isolate analyzed) and Zika virus (ZIKV; 2 isolates analyzed)) as well as an alphavirus (chikungunya virus; CHIKV; 2 isolates analyzed). Three different treatment regimens were evaluated, namely pre-treatment (only), post-treatment (only) and pre-and post-treatment, and three factors were evaluated, namely level of infection, virus titer and genome copy number. Results showed that all three treatment modalities were able to significantly reduce virus titer for all viruses investigated, with the exception of three isolates of DENV in the pre-treatment only regimen. Pre-and post-treatment was more effective in reducing the level of infection and genome copy number of all viruses investigated than either pre-treatment or post-treatment alone. collectively, these results suggest orlistat has potential as a broad-spectrum agent against multiple mosquito transmitted viruses.Mosquito transmitted viruses are a significant public health problem in many tropical and sub-tropical countries, and some of the most significant human pathogens belong to the genera Flavivirus and Alphavirus 1 . The genus Flavivirus consists of 53 virus species 2 of which more than half are transmitted by mosquitoes and the majority of these have the potential to infect humans 3 . Medically important mosquito transmitted viruses in the genus Flavivirus include dengue virus (DENV), Japanese encephalitis virus (JEV), Zika virus (ZIKV) and yellow fever virus (YFV). The genus Alphavirus consists of 31 virus species 2 the majority of which are spread by mosquitoes, and medically important alphaviruses include chikungunya virus (CHIKV), Ross River virus, Semliki Forest Virus and Sindbis virus 4 .Viruses in the genera Flavivirus and Alphavirus have a number of similarities. Viruses in both genera are classified in group IV in the Baltimore classification system 5 as they possess a positive sense single stranded RNA genome. The genome sizes are approximately equivalent (flaviviruses approximately 9.2-11 kb 6 , alphaviruses approximately 9.7-12 kb 7 , but while the ten flavivirus proteins (capsid (C), pre-membrane (prM), envelope (E), NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) are encoded by a single open reading frame, the nine alphavirus proteins are encoded by two open reading frames, the first of which encodes the non-structural proteins (nsP1, nsP2, nsP3 and nsP4), while the second open reading frame encodes the structural proteins (C, E1, E2, E3), as well as a protein (6 K) of uncertain function 4 . Viruses in both genera encode a protein with RNA-dependent RNA polymerase (RdRP) activity that undertakes gen...

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Section: Discussionmentioning

confidence: 99%

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

Hitakarun

Khongwichit

Wikan

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Orlistat and other FASN inhibitors have previously been examined for their anti-cancer and antiviral activities. Although the clinically approved oral administration of Orlistat does not result in its significant systemic distribution, pre-clinical studies in mice have demonstrated that systemic administration of Orlistat is well tolerated 47 .…”

Section: Vps34mentioning

confidence: 99%

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Silvas

Jureka

Nicolini

et al. 2020

Preprint

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Therapeutics targeting replication of SARS coronavirus 2 (SARS-CoV-2) are urgently needed. Coronaviruses rely on host membranes for entry, establishment of replication centers and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we tested small molecule inhibitors that target membrane dynamics or lipid metabolism. Included were inhibitors of the PI3 kinase VPS34, which functions in autophagy, endocytosis and other processes; Orlistat, an inhibitor of lipases and fatty acid synthetase, is approved by the FDA as a treatment for obesity; and Triacsin C which inhibits long chain fatty acyl-CoA synthetases. VPS34 inhibitors, Orlistat and Triacsin C inhibited virus growth in Vero E6 cells and in the human airway epithelial cell line Calu-3, acting at a post-entry step in the virus replication cycle. Of these the VPS34 inhibitors exhibit the most potent activity.

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“…Finally, fatty acid synthase (FASN) protein, a multifunctional enzyme that plays a central role in lipid synthesis, is particularly noteworthy in regard to glioma. This enzyme is often deregulated in several types of cancer [14] including GBM, in which its overexpression correlates with a more advanced disease stage [15]. FASN is also strongly expressed in patients with glioma stem cells (GSCs) and its inhibition reduces the expression of stem cell markers in favor of differentiation markers in GSCs [16].…”

Section: Introductionmentioning

confidence: 99%

Crocetin Extracted from Saffron Shows Antitumor Effects in Models of Human Glioblastoma

Colapietro

Mancini

Vitale

et al. 2020

IJMS

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Over recent years, many authors discussed the effects of different natural compounds on glioblastoma (GBM). Due to its capacity to impair survival and progression of different cancer types, saffron extract (SE), named crocetin (CCT), is particularly noteworthy. In this work, we elucidated the antitumor properties of crocetin in glioma in vivo and in vitro models for the first time. The in vitro results showed that the four tumor cell lines observed in this study (U251, U87, U138, and U373), which were treated with increasing doses of crocetin, showed antiproliferative and pro-differentiative effects as demonstrated by a significant reduction in the number of viable cells, deep changes in cell morphology, and the modulation of mesenchymal and neuronal markers. Indeed, crocetin decreased the expression of Cluster of Differentiation CD44, CD90, CXCR4, and OCT3/4 mesenchymal markers, but increased the expression of βIII-Tubulin and neurofilaments (NFH) neuronal linage-related markers. Epigenetic mechanisms may modulate these changes, since Histone Deacetylase, HDAC1 and HDAC3 were downmodulated in U251 and U87 cells, whereas HDAC1 expression was downmodulated in U138 and U373 cells. Western blotting analyses of Fatty Acid Synthase, FASN, and CD44 resulted in effective inhibition of these markers after CCT treatment, which was associated with important activation of the apoptosis program and reduced glioma cell movement and wound repair. The in vivo studies aligned with the results obtained in vitro. Indeed, crocetin was demonstrated to inhibit the growth of U251 and U87 cells that were subcutaneously injected into animal models. In particular, the Tumor To Progression or TTP values and Kaplan–Meier curves indicated that crocetin had more major effects than radiotherapy alone, but similar effects to temozolomide (TMZ). An intra-brain cell inoculation of a small number of luciferase-transfected U251 cells provided a model that was able to recapitulate recurrence after surgical tumor removal. The results obtained from the orthotopic intra-brain model indicated that CCT treatment increased the disease-free survival (DFS) and overall survival (OS) rates, inducing a delay in appearance of a detectable bioluminescent lesion. CCT showed greater efficacy than Radio Therapy (RT) but comparable efficacy to temozolomide in xenograft models. Therefore, we aimed to continue the study of crocetin’s effects in glioma disease, focusing our attention on the radiosensitizing properties of the natural compound and highlighting the ways in which this was realized.

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Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy

Cited by 101 publications

References 139 publications

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

Crocetin Extracted from Saffron Shows Antitumor Effects in Models of Human Glioblastoma

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