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ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand.
Rellinger EJ, Padmanabhan C, Qiao J, Appert A, Waterson AG, Lindsley CW, Beauchamp RD, Chung DH
(2017) Biochem Biophys Res Commun 491: 463-468
MeSH Terms: Antigens, CD, Antineoplastic Agents, Apoptosis, Cadherins, Caspase 3, Cell Cycle, Cell Line, Tumor, Drug Synergism, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Humans, Isoxazoles, Mesenchymal Stem Cells, Niacinamide, Poly(ADP-ribose) Polymerases, Sarcoma, Ewing, Signal Transduction, Small Molecule Libraries, TNF-Related Apoptosis-Inducing Ligand, Vimentin
Show Abstract · Added March 14, 2018
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Copyright © 2017 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib.
Wilson AJ, Sarfo-Kantanka K, Barrack T, Steck A, Saskowski J, Crispens MA, Khabele D
(2016) Gynecol Oncol 143: 143-151
MeSH Terms: Antineoplastic Agents, Cyclin E, DNA Repair, Drug Synergism, Female, Homologous Recombination, Humans, Hydroxamic Acids, Indoles, Oncogene Proteins, Ovarian Neoplasms, Panobinostat, Phthalazines, Piperazines
Show Abstract · Added March 4, 2019
OBJECTIVE - Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib.
METHODS - Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 in ovarian tumors and cell lines were extracted from The Cancer Genome Atlas (TCGA) and Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). In HR-proficient ovarian cancer cell line models (OVCAR-3, OVCAR-4, SKOV-3, and UWB1.289+BRCA1 wild-type), cell growth and viability were assessed by sulforhodamine B and xenograft assays. DNA damage and repair (pH2AX and RAD51 co-localization and DRGFP reporter activity) and apoptosis (cleaved PARP and cleaved caspase-3) were assessed by immunofluorescence and Western blot assays.
RESULTS - TCGA and CCLE data revealed positive correlations (Spearman) between cyclin E E2F1, and E2F1 gene targets related to DNA repair (BRCA1 and RAD51). Panobinostat downregulated cyclin E and HR repair pathway genes, and reduced HR efficiency in cyclin E-amplified OVCAR-3 cells. Further, panobinostat synergized with olaparib in reducing cell growth and viability in HR-proficient cells. Similar co-operative effects were observed in xenografts, and on pharmacodynamic markers of HR repair, DNA damage and apoptosis.
CONCLUSIONS - These results provide preclinical rationale for using HDACi to reduce HR in cyclin E-overexpressing and other types of HR-proficient ovarian cancer as a means of enhancing PARPi activity.
Copyright © 2016 Elsevier Inc. All rights reserved.
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MeSH Terms
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
Hubers SA, Brown NJ
(2016) Circulation 133: 1115-24
MeSH Terms: Abnormalities, Drug-Induced, Aminobutyrates, Angioedema, Angiotensin Receptor Antagonists, Biphenyl Compounds, Bradykinin, Contraindications, Drug Combinations, Drug Costs, Drug Synergism, Enalapril, Enzyme Inhibitors, Female, Follow-Up Studies, Heart Failure, Humans, Hyperkalemia, Hypertension, Kidney, Multicenter Studies as Topic, Natriuretic Peptides, Neprilysin, Pregnancy, Prodrugs, Prospective Studies, Pyridines, Randomized Controlled Trials as Topic, Stroke Volume, Tetrazoles, Thiazepines, Valsartan
Show Abstract · Added April 6, 2017
Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
© 2016 American Heart Association, Inc.
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31 MeSH Terms
EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer.
Amato KR, Wang S, Tan L, Hastings AK, Song W, Lovly CM, Meador CB, Ye F, Lu P, Balko JM, Colvin DC, Cates JM, Pao W, Gray NS, Chen J
(2016) Cancer Res 76: 305-18
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Benzamides, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Drug Synergism, ErbB Receptors, Erlotinib Hydrochloride, Humans, Lung Neoplasms, Mice, Mice, Nude, Niacinamide, Protein Kinase Inhibitors, Receptor, EphA2, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added January 26, 2016
Despite the success of treating EGFR-mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKI), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI-resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib-resistant tumor cells harboring EGFR(T790M) mutations in vitro and inhibited tumor growth and progression in an inducible EGFR(L858R+T790M)-mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib-resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small-molecule inhibitor ALW-II-41-27 decreased both survival and proliferation of erlotinib-resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third-generation EGFR TKI AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI-resistant, EGFR-mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI-resistant tumors.
©2016 American Association for Cancer Research.
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19 MeSH Terms
Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.
Rollins-Smith LA, Fites JS, Reinert LK, Shiakolas AR, Umile TP, Minbiole KP
(2015) Infect Immun 83: 4565-70
MeSH Terms: Adenosine, Animals, Apoptosis, Cell Survival, Chytridiomycota, Drug Synergism, Host-Pathogen Interactions, Humans, Jurkat Cells, Kynurenine, Lymphocytes, Mycoses, Skin, Thionucleosides, Tryptophan, Xenopus laevis
Show Abstract · Added April 18, 2017
Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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16 MeSH Terms
Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype.
Yamamoto S, Zhong J, Yancey PG, Zuo Y, Linton MF, Fazio S, Yang H, Narita I, Kon V
(2015) Atherosclerosis 242: 56-64
MeSH Terms: Angiotensin Receptor Antagonists, Animals, Aortic Diseases, Apolipoproteins E, Apoptosis, Atherosclerosis, Cell Line, Cytokines, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Synergism, Drug Therapy, Combination, Female, Hyperlipidemias, Inflammation, Losartan, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephrectomy, PPAR gamma, Phenotype, Pioglitazone, Renal Insufficiency, Chronic, Renin-Angiotensin System, Thiazolidinediones
Show Abstract · Added April 10, 2018
OBJECTIVE - Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model.
METHODS - Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response.
RESULTS - UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change.
CONCLUSION - Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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27 MeSH Terms
A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.
Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D
(2015) PLoS One 10: e0125482
MeSH Terms: Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Cell Survival, Cisplatin, DNA Repair, DNA-Directed DNA Polymerase, Drug Resistance, Neoplasm, Drug Synergism, Gene Library, HCT116 Cells, Humans, Intracellular Signaling Peptides and Proteins, Pyrazines, RNA, Small Interfering, Sulfones, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added February 4, 2016
The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.
1 Communities
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18 MeSH Terms
Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer.
Bhola NE, Jansen VM, Bafna S, Giltnane JM, Balko JM, Estrada MV, Meszoely I, Mayer I, Abramson V, Ye F, Sanders M, Dugger TC, Allen EV, Arteaga CL
(2015) Cancer Res 75: 405-14
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cell Cycle Proteins, Drug Synergism, Estradiol, Estrogen Receptor alpha, Female, Fulvestrant, Humans, MCF-7 Cells, Mice, Mice, Nude, Neoplasms, Hormone-Dependent, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Pteridines, RNA, Small Interfering, Random Allocation, Transcription Factors, Transcription, Genetic, Xenograft Model Antitumor Assays, bcl-X Protein
Show Abstract · Added January 20, 2015
Estrogen receptor (ER) α-positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER(+) breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER(+) human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy.
©2014 American Association for Cancer Research.
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23 MeSH Terms
Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM).
Morris LC, Nance KD, Gentry PR, Days EL, Weaver CD, Niswender CM, Thompson AD, Jones CK, Locuson CW, Morrison RD, Daniels JS, Niswender KD, Lindsley CW
(2014) J Med Chem 57: 10192-7
MeSH Terms: Allosteric Regulation, Animals, Catalepsy, Central Nervous System Agents, Drug Synergism, Exenatide, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Haloperidol, High-Throughput Screening Assays, Indoles, Insulin, Insulin Secretion, Islets of Langerhans, Male, Mice, Inbred C57BL, Microsomes, Liver, Peptides, Pyrrolidines, Receptors, Glucagon, Structure-Activity Relationship, Venoms
Show Abstract · Added February 16, 2015
A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.
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22 MeSH Terms
LYN-activating mutations mediate antiestrogen resistance in estrogen receptor-positive breast cancer.
Schwarz LJ, Fox EM, Balko JM, Garrett JT, Kuba MG, Estrada MV, González-Angulo AM, Mills GB, Red-Brewer M, Mayer IA, Abramson V, Rizzo M, Kelley MC, Meszoely IM, Arteaga CL
(2014) J Clin Invest 124: 5490-502
MeSH Terms: Amino Acid Substitution, Aminopyridines, Animals, Breast Neoplasms, Dasatinib, Drug Resistance, Neoplasm, Drug Synergism, Estrogen Receptor Modulators, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Nude, Morpholines, Mutation, Missense, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, Receptors, Estrogen, Thiazoles, Xenograft Model Antitumor Assays, src Homology Domains, src-Family Kinases
Show Abstract · Added February 16, 2016
Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.
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25 MeSH Terms