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Article: Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Hameed, Kanwal M / Bollino, Dominique R / Shetty, Amol C / Carter-Cooper, Brandon / Lapidus, Rena G / Emadi, Ashkan

2024 Volume 14, Page(s) 1326754

Abstract: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic ... ...

Abstract	Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with
Language	English
Publishing date	2024-04-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2024.1326754
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Article ; Online: Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles.

Emadi, Ashkan / Lapidus, Rena G

Journal of the National Cancer Institute

2018 Volume 109, Issue 11

MeSH term(s)	Humans ; Mitochondria/metabolism ; Neoplasms/therapy ; Oxidative Phosphorylation
Language	English
Publishing date	2018-01-24
Publishing country	United States
Document type	Editorial
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djx069
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Article: A novel XBP1 variant is highly enriched in cancer tissues and is specifically required for cancer cell survival

Zhong, Yongwang / Yan, Wenjing / Ruan, Jingjing / Fang, Mike / Lapidus, Rena G / Du, Shaojun / Fang, Shengyun

Biochemical and biophysical research communications. 2021 July 12, v. 562

2021

Abstract: XBP1 is a basic leucine zipper (bZIP) transcription factor and a key mediator of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR). XBP1-mediated transcription facilitates cell adaptation to ER stress and also promotes tumor ...

Abstract	XBP1 is a basic leucine zipper (bZIP) transcription factor and a key mediator of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR). XBP1-mediated transcription facilitates cell adaptation to ER stress and also promotes tumor progression, while suppressing anti-tumor immunity. Here we report a novel XBP1 variant, namely XBP1 variant 1 (XBP1v1, Xv1 for short), that is specifically required for survival of cancer cells. Xv1 contains a cryptic first exon that is conserved only in humans and great apes. Comparing to XBP1, Xv1 encodes a protein with a different N-terminal sequence containing 25 amino acids. Analysis of RNAseq database reveals that Xv1 is broadly expressed across cancer types but almost none in normal tissues. Elevated Xv1 expression is associated with poor survival of patients with several types of cancer. Knockdown of Xv1 induces death of multiple cancer cell lines but has little effect on non-cancerous cells in vitro. Moreover, knockdown of Xv1 also inhibits growth of a xenograft breast tumor in mice. Together, our results indicate that Xv1 is essential for survival of cancer cells.
Keywords	breast neoplasms ; cell viability ; databases ; death ; endoplasmic reticulum ; exons ; immunity ; leucine zipper ; neoplasm cells ; neoplasm progression ; research ; transcription factors ; unfolded protein response ; xenotransplantation
Language	English
Dates of publication	2021-0712
Size	p. 69-75.
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.05.038
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Article ; Online: Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma.

Yang, Zejia / Liao, Jipei / Lapidus, Rena G / Fan, Xiaoxuan / Mehra, Ranee / Cullen, Kevin J / Dan, Hancai

Cancer chemotherapy and pharmacology

2022 Volume 89, Issue 4, Page(s) 469–478

Abstract: Purpose: We investigated the role of Wee1 kinase in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines and determined the efficacy of either Wee1 inhibitor, AZD1775 alone, or in combination ...

Abstract	Purpose: We investigated the role of Wee1 kinase in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines and determined the efficacy of either Wee1 inhibitor, AZD1775 alone, or in combination with cisplatin, on cisplatin-resistant HNSCC inhibition. Methods: Phosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell viability and apoptosis were examined by MTS assay and flow cytometry, respectively. Results: Wee1 kinase protein expression levels in five cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin-sensitive partners. Importantly, Wee1 knockdown inhibited cell proliferation and re-sensitized cells to cisplatin treatment. Interestingly, previous studies have also shown that Wee1 inhibitor AZD1775 synergizes with cisplatin to suppress cell proliferation of cisplatin-sensitive HNSCC. We found that AZD1775 inhibited both cisplatin-sensitive and resistant HNSCC with similar IC Conclusion: Wee1 inhibitor, AZD1775, and cisplatin coordinately suppressed proliferation and survival of HNSCC.
MeSH term(s)	Apoptosis ; Cell Cycle Proteins/genetics ; Cell Line, Tumor ; Cell Proliferation ; Cisplatin/pharmacology ; Head and Neck Neoplasms/drug therapy ; Humans ; Protein-Tyrosine Kinases ; Squamous Cell Carcinoma of Head and Neck/drug therapy
Chemical Substances	Cell Cycle Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; WEE1 protein, human (EC 2.7.10.2) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-02-25
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-022-04410-w
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Article ; Online: Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics.

Lee, Michelle H / Lapidus, Rena G / Ferraris, Dana / Emadi, Ashkan

Molecules (Basel, Switzerland)

2019 Volume 24, Issue 17

Abstract: Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to ... ...

Abstract	Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.
MeSH term(s)	Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Naphthoquinones/pharmacology ; Naphthoquinones/therapeutic use ; Reactive Oxygen Species/metabolism
Chemical Substances	Naphthoquinones ; Reactive Oxygen Species
Language	English
Publishing date	2019-08-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules24173121
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Article ; Online: Exploiting epigenetically mediated changes: Acute myeloid leukemia, leukemia stem cells and the bone marrow microenvironment.

Kogan, Aksinija A / Lapidus, Rena G / Baer, Maria R / Rassool, Feyruz V

Advances in cancer research

2019 Volume 141, Page(s) 213–253

Abstract: Acute myeloid leukemia (AML) derives from the clonal expansion of immature myeloid cells in the bone marrow, and results in the disruption of normal hematopoiesis and subsequent bone marrow failure. The bone marrow microenvironment (BME) and its immune ... ...

Abstract	Acute myeloid leukemia (AML) derives from the clonal expansion of immature myeloid cells in the bone marrow, and results in the disruption of normal hematopoiesis and subsequent bone marrow failure. The bone marrow microenvironment (BME) and its immune and other supporting cells are regarded to facilitate the survival, differentiation and proliferation of leukemia stem cells (LSCs), which enables AML cells to persist and expand despite treatment. Recent studies have identified epigenetic modifications among AML cells and BME constituents in AML, and have shown that epigenetic therapy can potentially reprogram these alterations. In this review, we summarize the interactions between the BME and LSCs, and discuss changes in how the BME and immune cells interact with AML cells. After describing the epigenetic modifications seen across chromatin, DNA, the BME, and the immune microenvironment, we explore how demethylating agents may reprogram these pathological interactions, and potentially re-sensitize AML cells to treatment.
MeSH term(s)	Animals ; Bone Marrow/pathology ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/immunology ; Leukemia, Myeloid, Acute/pathology ; Neoplastic Stem Cells/immunology ; Neoplastic Stem Cells/pathology ; Tumor Microenvironment/immunology
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/bs.acr.2018.12.005
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Article ; Online: A novel XBP1 variant is highly enriched in cancer tissues and is specifically required for cancer cell survival.

Zhong, Yongwang / Yan, Wenjing / Ruan, Jingjing / Fang, Mike / Lapidus, Rena G / Du, Shaojun / Fang, Shengyun

Biochemical and biophysical research communications

2021 Volume 562, Page(s) 69–75

Abstract	XBP1 is a basic leucine zipper (bZIP) transcription factor and a key mediator of the endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR). XBP1-mediated transcription facilitates cell adaptation to ER stress and also promotes tumor progression, while suppressing anti-tumor immunity. Here we report a novel XBP1 variant, namely XBP1 variant 1 (XBP1v1, Xv1 for short), that is specifically required for survival of cancer cells. Xv1 contains a cryptic first exon that is conserved only in humans and great apes. Comparing to XBP1, Xv1 encodes a protein with a different N-terminal sequence containing 25 amino acids. Analysis of RNAseq database reveals that Xv1 is broadly expressed across cancer types but almost none in normal tissues. Elevated Xv1 expression is associated with poor survival of patients with several types of cancer. Knockdown of Xv1 induces death of multiple cancer cell lines but has little effect on non-cancerous cells in vitro. Moreover, knockdown of Xv1 also inhibits growth of a xenograft breast tumor in mice. Together, our results indicate that Xv1 is essential for survival of cancer cells.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Survival/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Variation ; Humans ; Mice, Nude ; Neoplasms/genetics ; Neoplasms/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; X-Box Binding Protein 1/genetics ; Xenograft Model Antitumor Assays ; Mice
Chemical Substances	RNA, Messenger ; X-Box Binding Protein 1
Language	English
Publishing date	2021-05-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2021.05.038
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Article ; Online: Selective targeting of metastatic ovarian cancer using an engineered anthrax prodrug activated by membrane-anchored serine proteases.

Duru, Nadire / Pawar, Nisha R / Martin, Erik W / Buzza, Marguerite S / Conway, Gregory D / Lapidus, Rena G / Liu, Shihui / Reader, Jocelyn / Rao, Gautam G / Roque, Dana M / Leppla, Stephen H / Antalis, Toni M

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 28, Page(s) e2201423119

Abstract: Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered ... ...

Abstract	Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.
MeSH term(s)	Antigens, Bacterial/pharmacology ; Antigens, Bacterial/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Bacterial Toxins/pharmacology ; Bacterial Toxins/therapeutic use ; Cell Line, Tumor ; Enzyme Precursors/metabolism ; Female ; Humans ; Neoplasm Recurrence, Local ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Serine Proteases/metabolism ; Spheroids, Cellular ; Xenograft Model Antitumor Assays
Chemical Substances	Antigens, Bacterial ; Antineoplastic Agents ; Bacterial Toxins ; Enzyme Precursors ; Prodrugs ; anthrax toxin ; Serine Proteases (EC 3.4.-)
Language	English
Publishing date	2022-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2201423119
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Article ; Online: Phase I Clinical Trial of DNA Methyltransferase Inhibitor Decitabine and PARP Inhibitor Talazoparib Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia.

Baer, Maria R / Kogan, Aksinija A / Bentzen, Søren M / Mi, Tian / Lapidus, Rena G / Duong, Vu H / Emadi, Ashkan / Niyongere, Sandrine / O'Connell, Casey L / Youngblood, Benjamin A / Baylin, Stephen B / Rassool, Feyruz V

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 7, Page(s) 1313–1322

Abstract: Purpose: Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island ... ...

Abstract	Purpose: Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here, we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in relapsed/refractory AML. Patients and methods: Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on cycle 1 days 1 (pretreatment), 5 and 8 blood blasts. Results: Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3-5 events included fever in 19 patients and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) and hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci, and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine. Conclusions: Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols ; Azacitidine ; DNA ; Decitabine/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Methyltransferases ; Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
Chemical Substances	Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Decitabine (776B62CQ27) ; DNA (9007-49-2) ; talazoparib (9QHX048FRV) ; Methyltransferases (EC 2.1.1.-) ; Azacitidine (M801H13NRU)
Language	English
Publishing date	2022-01-28
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-21-3729
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Article ; Online: Translatome changes in acute myeloid leukemia cells post exposure to pegcrisantaspase and venetoclax.

Kapadia, Bandish / Shetty, Amol C / Bollino, Dominique / Bhandary, Binny / Lapidus, Rena G / Mahmood, Kanwal / Mahurkar, Anup / Gartenhaus, Ronald B / Eckert, Richard L / Emadi, Ashkan

Experimental hematology

2022 Volume 108, Page(s) 55–63

Abstract: The clinical outcomes of patients with acute myeloid leukemia (AML) treated with available therapy remain unsatisfactory. We recently reported that the BCL-2 inhibitor venetoclax synergizes with pegcrisantaspase (Ven-PegC) and exhibits remarkable in vivo ...

Abstract	The clinical outcomes of patients with acute myeloid leukemia (AML) treated with available therapy remain unsatisfactory. We recently reported that the BCL-2 inhibitor venetoclax synergizes with pegcrisantaspase (Ven-PegC) and exhibits remarkable in vivo efficacy in a preclinical model of AML with complex karyotype. The Ven-PegC combination blocks synthesis of proteins in AML cells by inhibiting cap-dependent translation of mRNA. To further explore the impact of Ven-PegC on protein translation, we used polysome profiling and high-throughput RNA sequencing to characterize Ven-PegC-dependent changes to the translatome. Here we report that the translation of five mRNAs, including two microRNAs, one rRNA, and two mitochondrial genes, was altered after exposure to all three treatments (Ven, PegC, and Ven-PegC). We focused our translatome validation studies on six additional genes related to translational efficiency that were modified by Ven-PegC. Notably, Ven-PegC treatment increased the RNA translation and protein levels of Tribbles homologue 3 (TRIB3), eukaryotic translation initiation factor 3 subunit C (eIF3C), doublesex and mab-3-related transcription factor 1 (DMRT1), and salt-inducible kinase 1 (SIK1). We validated the observed changes in gene/protein expression in vitro and confirmed our cell line-based studies in the bone marrow of an AML patient-derived xenograft model after Ven-PegC treatment. These results support examining alterations in the translatome post chemotherapy to offer insight into the drug's mechanism of action and to inform future therapeutic decisions.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use
Chemical Substances	Bridged Bicyclo Compounds, Heterocyclic ; Sulfonamides ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2022-01-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2022.01.006
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