Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 379

Publication Record

Connections

Tyrosine Kinase Inhibitors in Leukemia and Cardiovascular Events: From Mechanism to Patient Care.
Manouchehri A, Kanu E, Mauro MJ, Aday AW, Lindner JR, Moslehi J
(2020) Arterioscler Thromb Vasc Biol 40: 301-308
MeSH Terms: Cardiovascular Diseases, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Patient Care, Protein Kinase Inhibitors, Protein-Tyrosine Kinases
Show Abstract · Added January 15, 2020
Targeted oncology therapies have revolutionized cancer treatment over the last decade and have resulted in improved prognosis for many patients. This advance has emanated from elucidation of pathways responsible for tumorigenesis followed by targeting of these pathways by specific molecules. Cardiovascular care has become an increasingly critical aspect of patient care in part because patients live longer, but also due to potential associated toxicities from these therapies. Because of the targeted nature of cancer therapies, cardiac and vascular side effects may additionally provide insights into the basic biology of vascular disease. We herein provide the example of tyrosine kinase inhibitors utilized in chronic myelogenous leukemia to illustrate this medical transformation. We describe the vascular considerations for the clinical care of chronic myelogenous leukemia patients as well as the emerging literature on mechanisms of toxicities of the individual tyrosine kinase inhibitors. We additionally postulate that basic insights into toxicities of novel cancer therapies may serve as a new platform for investigation in vascular biology and a new translational research opportunity in vascular medicine.
0 Communities
1 Members
0 Resources
6 MeSH Terms
High prevalence of antibiotic allergies in cladribine-treated patients with hairy cell leukemia - lessons for immunopathogenesis and prescribing.
Meher-Homji Z, Tam CS, Siderov J, Seymour JF, Holmes NE, Chua KYL, Phillips EJ, Slavin MA, Trubiano JA
(2019) Leuk Lymphoma 60: 3455-3460
MeSH Terms: Adult, Aged, Anti-Bacterial Agents, Antineoplastic Combined Chemotherapy Protocols, Australia, Case-Control Studies, Cladribine, Drug Hypersensitivity, Female, Follow-Up Studies, Humans, Leukemia, Hairy Cell, Male, Middle Aged, Prevalence, Prognosis, Retrospective Studies, Survival Rate, Vidarabine
Show Abstract · Added March 30, 2020
The relationship between hematological malignancy and chemotherapy on the prevalence of antibiotic allergy label (AAL) is ill-defined. We performed a multicenter retrospective case-control study comparing AAL rates among cladribine-treated hairy cell leukemia (C-HCL) cases, non-HCL cladribine-treated controls (control-1), and fludarabine-treated controls (control-2). The prevalence of AALs in C-HCL patients was 60%, compared with control-1 (14%,  < .01) and control-2 patients (25%,  < .01). The predominant phenotype was maculopapular exanthem (92%). The drugs implicated in AAL causality in C-HCL patients included beta-lactams (81%), trimethoprim-sulfamethoxazole (58%), and allopurinol (69%). C-HCL patients demonstrate high rates of AAL, potentially due to immune dysregulation, impacting beta-lactam utilization.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer.
Lee T, Christov PP, Shaw S, Tarr JC, Zhao B, Veerasamy N, Jeon KO, Mills JJ, Bian Z, Sensintaffar JL, Arnold AL, Fogarty SA, Perry E, Ramsey HE, Cook RS, Hollingshead M, Davis Millin M, Lee KM, Koss B, Budhraja A, Opferman JT, Kim K, Arteaga CL, Moore WJ, Olejniczak ET, Savona MR, Fesik SW
(2019) J Med Chem 62: 3971-3988
MeSH Terms: Animals, Antineoplastic Agents, Azepines, Binding Sites, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Drug Evaluation, Preclinical, Female, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Dynamics Simulation, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Protein Structure, Tertiary, Small Molecule Libraries, Structure-Activity Relationship, Xenograft Model Antitumor Assays
Show Abstract · Added April 15, 2019
Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition could serve as a strategy to target cancers that require Mcl-1 to evade apoptosis. Herein, we describe the use of structure-based design to discover a novel compound (42) that robustly and specifically inhibits Mcl-1 in cell culture and animal xenograft models. Compound 42 binds to Mcl-1 with picomolar affinity and inhibited growth of Mcl-1-dependent tumor cell lines in the nanomolar range. Compound 42 also inhibited the growth of hematological and triple negative breast cancer xenografts at well-tolerated doses. These findings highlight the use of structure-based design to identify small molecule Mcl-1 inhibitors and support the use of 42 as a potential treatment strategy to block Mcl-1 activity and induce apoptosis in Mcl-1-dependent cancers.
0 Communities
1 Members
0 Resources
20 MeSH Terms
A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells.
Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, Beckermann KE, Gama V
(2018) Stem Cell Reports 10: 684-692
MeSH Terms: Apoptosis, Cell Differentiation, Cell Line, Cellular Reprogramming, Humans, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membranes, Myeloid Cell Leukemia Sequence 1 Protein, Pluripotent Stem Cells, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added March 14, 2018
Human pluripotent stem cells (hPSCs) maintain a highly fragmented mitochondrial network, but the mechanisms regulating this phenotype remain unknown. Here, we describe a non-cell death function of the anti-apoptotic protein, MCL-1, in regulating mitochondrial dynamics and promoting pluripotency of stem cells. MCL-1 is induced upon reprogramming, and its inhibition or knockdown induces dramatic changes to the mitochondrial network as well as loss of the key pluripotency transcription factors, NANOG and OCT4. Aside from localizing at the outer mitochondrial membrane like other BCL-2 family members, MCL-1 is unique in that it also resides at the mitochondrial matrix in pluripotent stem cells. Mechanistically, we find MCL-1 to interact with DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Depletion of MCL-1 compromised the levels and activity of these key regulators of mitochondrial dynamics. Our findings uncover an unexpected, non-apoptotic function for MCL-1 in the maintenance of mitochondrial structure and stemness.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers.
Williams MM, Lee L, Werfel T, Joly MMM, Hicks DJ, Rahman B, Elion D, McKernan C, Sanchez V, Estrada MV, Massarweh S, Elledge R, Duvall C, Cook RS
(2018) Cell Death Dis 9: 21
MeSH Terms: Aniline Compounds, Animals, Apoptosis, Breast Neoplasms, Cell Line, Tumor, Down-Regulation, Estrogen Antagonists, Female, Fulvestrant, Gene Targeting, Humans, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Receptors, Estrogen, Signal Transduction, Sulfonamides, Up-Regulation, bcl-X Protein
Show Abstract · Added March 14, 2018
Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
Earl DC, Ferrell PB, Leelatian N, Froese JT, Reisman BJ, Irish JM, Bachmann BO
(2018) Nat Commun 9: 39
MeSH Terms: Aged, Bone Marrow, Cell Extracts, Chromatography, Liquid, DNA Damage, Female, Flow Cytometry, Humans, Leukemia, Leukemia, Myeloid, Acute, Lymphocytes, Male, Mass Spectrometry, Metabolome, Metabolomics, Monocytes, Signal Transduction, Streptomyces, Tumor Cells, Cultured, Young Adult
Show Abstract · Added January 4, 2018
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
3 Communities
1 Members
0 Resources
20 MeSH Terms
Cardiovascular care of patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI) therapy.
Barber MC, Mauro MJ, Moslehi J
(2017) Hematology Am Soc Hematol Educ Program 2017: 110-114
MeSH Terms: Aged, Dasatinib, Female, Fusion Proteins, bcr-abl, Humans, Hypertension, Pulmonary, Imidazoles, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Protein Kinase Inhibitors, Pyridazines, Pyrimidines
Show Abstract · Added April 22, 2018
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission." Importantly, later-generation BCR-ABL1 TKIs have been associated with CV complications. Dasatinib has been associated with pleural/pericardial effusions and pulmonary hypertension, whereas nilotinib and ponatinib have been linked to the development of vascular occlusive events. There is currently a dearth of data with respect to the mechanisms of drug toxicities, the subsets of patients at risk, and prevention and treatment strategies to mitigate CV complications in patients with CML. Nevertheless, optimal patient CV risk assessment needs to become a more central tenet of patient care in CML. We propose several practical considerations for the practicing oncologist relative to the CV health of patients with CML, especially those on chronic TKI therapy.
© 2016 by The American Society of Hematology. All rights reserved.
0 Communities
1 Members
0 Resources
13 MeSH Terms
MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation.
Lee KM, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sánchez V, Sanders ME, Lee T, Gómez H, Lluch A, Pérez-Fidalgo JA, Wolf MM, Andrejeva G, Rathmell JC, Fesik SW, Arteaga CL
(2017) Cell Metab 26: 633-647.e7
MeSH Terms: Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Humans, Mice, Nude, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplastic Stem Cells, Oxidative Phosphorylation, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels, and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that (1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS and (2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.
Copyright © 2017. Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Ventricular arrhythmias and sudden death in patients taking ibrutinib.
Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, Jones JA, Walewska R, Savage KJ, Michaud GF, Moslehi JJ, Brown JR
(2017) Blood 129: 2581-2584
MeSH Terms: Arrhythmias, Cardiac, Death, Sudden, Cardiac, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Pyrazoles, Pyrimidines
Added March 26, 2017
0 Communities
1 Members
0 Resources
8 MeSH Terms
Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, McKernan C, Sanchez V, Balko JM, Stricker T, Estrada MV, Cook RS
(2017) Mol Cancer Res 15: 259-268
MeSH Terms: Aniline Compounds, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Estrogen Receptor alpha, Female, Humans, MCF-7 Cells, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Sulfonamides, bcl-X Protein
Show Abstract · Added April 6, 2017
An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of as compared with or (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured using Mcl-1/Bim proximity ligation assays. Importantly, gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of or and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing. Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. .
©2016 American Association for Cancer Research.
0 Communities
2 Members
0 Resources
15 MeSH Terms