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Dive into the research topics where Yanina Eberhard is active.

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Featured researches published by Yanina Eberhard.


Cancer Cell | 2011

INHIBITION OF MITOCHONDRIAL TRANSLATION AS A THERAPEUTIC STRATEGY FOR HUMAN ACUTE MYELOID LEUKEMIA

Marko Skrtic; Shrivani Sriskanthadevan; Bozhena Jhas; Marinella Gebbia; Xiaoming Wang; Zezhou Wang; Rose Hurren; Yulia Jitkova; Marcela Gronda; Neil MacLean; Courteney Lai; Yanina Eberhard; Justyna Bartoszko; Paul A. Spagnuolo; Angela Rutledge; Alessandro Datti; Troy Ketela; Jason Moffat; Brian H. Robinson; Jessie H. Cameron; Jeffery L. Wrana; Connie J. Eaves; Mark D. Minden; Jean C.Y. Wang; John E. Dick; Keith Humphries; Corey Nislow; Guri Giaever; Aaron D. Schimmer

To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.


Blood | 2009

Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells

Yanina Eberhard; Sean P. McDermott; Xiaoming Wang; Marcela Gronda; Amudha Venugopal; Tabitha E. Wood; Rose Hurren; Alessandro Datti; Robert A. Batey; Jeffrey L. Wrana; William E. Antholine; John E. Dick; Aaron D. Schimmer

Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma.


Molecular Cancer Therapeutics | 2008

A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death

Tabitha E. Wood; Shadi Dalili; Craig D. Simpson; Rose Hurren; Xinliang Mao; Fernando Suarez Saiz; Marcela Gronda; Yanina Eberhard; Mark D. Minden; Philip J. Bilan; Amira Klip; Robert A. Batey; Aaron D. Schimmer

Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands. [Mol Cancer Ther 2008;7(11):3546–55]


Molecular Cancer Therapeutics | 2010

Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

Tabitha E. Wood; Shadi Dalili; Craig D. Simpson; Mahadeo A. Sukhai; Rose Hurren; Kika Anyiwe; Xinliang Mao; Fernando Suarez Saiz; Marcela Gronda; Yanina Eberhard; Neil MacLean; Troy Ketela; John C. Reed; Jason Moffat; Mark D. Minden; Robert A. Batey; Aaron D. Schimmer

Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56


Apoptosis | 2012

A genome wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of anoikis resistance

Craig D. Simpson; Rose Hurren; Dahlia Kasimer; Neil MacLean; Yanina Eberhard; Troy Ketela; Jason Moffat; Aaron D. Schimmer

Acquisition of resistance to anchorage dependant cell death, a process termed anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of anoikis resistance and sensitivity are poorly understood. To better understand resistance to anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render anoikis-sensitive RWPE-1 prostate cells resistant to anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited anoikis in RWPE-1 cells as well as anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho-N-acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of anoikis sensitivity.


Molecular Cancer Therapeutics | 2011

Abstract A22: A genome-wide shRNA screen identifies α/β hydrolase domain containing 4 (ABHD4) as a novel regulator of anoikis resistance.

Craig D. Simpson; Rose Hurren; Neil MacLean; Yanina Eberhard; Troy Ketela; Jason Moffat; Aaron D. Schimmer

Acquisition of resistance to anchorage dependant cell death, a process termed anoikis, is a requirement for cancer cell metastasis. However, the molecular determinants of anoikis resistance and sensitivity are poorly understood. To better understand resistance to anoikis we conducted a genome wide lentiviral shRNA screen to identify genes whose knockdown render anoikis-sensitive RWPE-1 prostate cells resistant to anoikis. RWPE-1 cells were infected with a pooled lentiviral shRNA library with 54,021 shRNA targeting 11,255 genes. After infection, an anoikis-resistant cell population was selected and shRNA sequences were amplified and sequenced. Thirty-four shRNA sequences reproducibly protected RWPE-1 cells from anoikis after culture under suspension conditions including the top validated hit, α/β hydrolase domain containing 4 (ABHD4). In validation studies, ABHD4 knockdown inhibited anoikis in RWPE-1 cells as well as anoikis sensitive NP69 nasopharyngeal and OVCAR3 ovarian cancer cells, while over-expression of the gene increased sensitivity. Induction of anoikis after ABHD4 knockdown was associated with cleavage of PARP and activation of caspases-3, but was independent in changes of FLIP, FAK and Src expression. Interestingly, induction of anoikis after ABHD4 knockdown was independent of the known role of ABHD4 in the anandamide synthesis pathway and the generation of glycerophospho-N-acyl ethanolamines. Thus, ABHD4 is a novel genetic regulator of anoikis sensitivity.


Blood | 2007

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

Xinliang Mao; A. Keith Stewart; Rose Hurren; Alessandro Datti; Xuegong Zhu; Yuanxiao Zhu; Chang-Xin Shi; Kyle Lee; Rodger Tiedemann; Yanina Eberhard; Suzanne Trudel; Shengben Liang; Seth J. Corey; Lisa C. Gillis; Dwayne L. Barber; Jeffery L. Wrana; Shereen Ezzat; Aaron D. Schimmer


Oncotarget | 2011

Inhibition of SREBP1 sensitizes cells to death ligands

Yanina Eberhard; Marcela Gronda; Rose Hurren; Alessandro Datti; Neil MacLean; Troy Ketela; Jason Moffat; Jeffrey L. Wrana; Aaron D. Schimmer


Blood | 2011

Inhibition of Mitochondrial Translation As a Therapeutic Strategy for Acute Myeloid Leukemia (AML)

Marko Skrtic; Shrivani Sriskanthadevan; Bozhena Livak; Marinella Gebbia; Xiaoming Wang; Zezhou Wang; Rose Hurren; Yulia Jitkova; Marcela Gronda; Neil MacLean; Courteney Lai; Yanina Eberhard; Justyna Bartoszko; Paul A. Spagnuolo; Angela Rutledge; Alessandro Datti; Troy Ketela; Jason Moffat; Brian H. Robinson; Jessie M. Cameron; Jeff Wrana; Connie J. Eaves; Mark D. Minden; Jean C.Y. Wang; John E. Dick; R. Keith Humphries; Corey Nislow; Guri Giaever; Aaron D. Schimmer


Archive | 2010

up-regulation of ubiquitin expression by increasing its proteasomal degradation through A chemical biology screen identifies glucocorticoids that regulate c-maf

Seth J. Corey; Lisa C. Gillis; Dwayne L. Barber; Jeffery L. Wrana; Shereen Ezzat; Aaron D. Changxin Shi; Kyle Lee; Rodger Tiedemann; Yanina Eberhard; Suzanne Trudel; Shengben Liang; Xinliang Mao; A. Keith Stewart; Rose Hurren; Alessandro Datti; Xuegong Zhu; Yuan-Xiao Zhu

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Rose Hurren

Princess Margaret Cancer Centre

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Aaron D. Schimmer

Princess Margaret Cancer Centre

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Marcela Gronda

Princess Margaret Cancer Centre

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Neil MacLean

Princess Margaret Cancer Centre

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Craig D. Simpson

Ontario Institute for Cancer Research

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Mark D. Minden

Princess Margaret Cancer Centre

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Xiaoming Wang

Princess Margaret Cancer Centre

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John E. Dick

Princess Margaret Cancer Centre

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