Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

Alwarawrah, Yazan; Hughes, Philip F.; Loiselle, David R.; Carlson, David A.; Darr, David B.; Jordan, Jamie L.; Xiong, Jessie; Hunter, Lucas; Dubois, Laura G.; Thompson, J. Will; Kulkarni, Milind V.; Ratcliff, Annette N.; Kwiek, Jesse J.; Haystead, Timothy A.J.

doi:10.1016/j.chembiol.2016.04.011

Cited by 126 publications

(128 citation statements)

References 44 publications

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“…As a case study, we used the developed platform to study the response to metformin treatment, which preliminarily suggested metformin has differential effects on different lipid classes. In the presence of lipid-rich medium, certain lipids accumulated after metformin treatment, which is consistent with a recent study showing that the certain classes of lipids accumulated in breast cancer cells after treatment with a fatty acid synthase inhibitor (20). Further, as a proof of concept we measured with stable isotopes, the incorporation of glucose into lipids.…”

Section: Discussionsupporting

confidence: 90%

Quantitative evaluation of a high resolution lipidomics platform

Liu

Xiao

et al. 2019

Preprint

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Given the general importance of lipids in health and disease, there is a need for efficient technology that broadly profiles and quantitates the lipid composition of complex mixtures.In this study, we developed and quantitatively evaluated a platform that simultaneously profiles both lipids and polar metabolites from the same sample. This method was achieved by using a methyl tert-butyl ether (MTBE) extraction and employing two liquid chromatography methods coupled with high resolution mass spectrometry (LC-HRMS). This workflow enabled detection and semi-quantitationof over 300 polar metabolites as well as over 300 lipids with comprehensive coverage of diverse chemical classes. Using cultured mammalian cells as an example, we report the quantitative properties of the platform including the sensitivity and linear range. The lipidomics strategy was further applied to characterize changes to lipid metabolism upon treatment with metformin to human ovarian cancer cells. Of the 256 detected lipids, 99 lipids (39%) significantly increased, 11 lipids (4%) were significantly reduced and 146 lipids (57%) remain unchanged in metformin-treated cells. Stable isotope tracing of carbon into lipids using [ 13 C6]-glucose further measured the contribution of de novo fatty acid synthesis to the total fatty acid pool. In summary, the platform enabled the semi-quantitative assessment of hundreds of lipid species and associated carbon incorporation from glucose in a high throughput manner.

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Section: Discussionsupporting

confidence: 90%

Quantitative evaluation of a high resolution lipidomics platform

Liu

Xiao

et al. 2019

Preprint

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“…As a control, MDA-MB-231 cells were treated with Takinib but not TNFα. Caspase 3/7 activity was determined as previously described (Alwarawrah et al, 2016). TNFα stimulation in the presence of Takinib induced caspase activity in MDA-MB-231cells in a dose-dependent manner, whereas unstimulated cells did not upregulate caspase activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The assay was performed as previously described (Alwarawrah et al, 2016; Howe et al, 2014). Cells were seeded at a density of 5,000 cells/well.…”

Section: Star Methodsmentioning

confidence: 99%

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Totzke

Gurbani

Raphemot

et al. 2017

Cell Chemical Biology

112

121

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Summary Tumor necrosis factor α (TNFα) has both positive and negative roles in human disease. In certain cancers, TNFα is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNFα antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNFα-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNFα stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated TAK1 that binds within the ATP binding pocket, yet is non-competitive, and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNFα-induced cell death, with general implications for cancer and autoimmune disease treatment.

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“…In addition, an antimicrobial agent triclosan42 and GSK219406943 have been shown to have a potent inhibitory activity in FASN. Recently, Alwarawrah et al44 showed that Fasnall, a novel thiophenopyrimidine-based FASN inhibitor, exerts potent antitumor activity against various breast cancer cell lines and is well tolerated in mice. Moreover, Fasnall reduces tumor volume and increases survival in a mouse breast cancer model.…”

Section: Anticancer Agents Targeting Lipid Metabolic Reprogrammingmentioning

confidence: 99%

Targeting Lipid Metabolic Reprogramming as Anticancer Therapeutics

Young

Lee

2016

J Cancer Prev

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Cancer cells rewire their metabolism to satisfy the demands of growth and survival, and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. Lipid metabolism is pivotal in cellular process that converts nutrients into energy, building blocks for membrane biogenesis and the generation of signaling molecules. Accumulating evidence suggests that cancer cells show alterations in different aspects of lipid metabolism. The changes in lipid metabolism of cancer cells can affect numerous cellular processes, including cell growth, proliferation, differentiation, and survival. The potential dependence of cancer cells on the deregulated lipid metabolism suggests that enzymes and regulating factors involved in this process are promising targets for cancer treatment. In this review, we focus on the features associated with the lipid metabolic pathways in cancer, and highlight recent advances on the therapeutic targets of specific lipid metabolic enzymes or regulating factors and target-directed small molecules that can be potentially used as anticancer drugs.

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Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

Cited by 126 publications

References 44 publications

Quantitative evaluation of a high resolution lipidomics platform

Quantitative evaluation of a high resolution lipidomics platform

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease

Targeting Lipid Metabolic Reprogramming as Anticancer Therapeutics

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