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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
Multiresponsive Nanogels for Targeted Anticancer Drug Delivery.
Zhang Q, Colazo J, Berg D, Mugo SM, Serpe MJ
(2017) Mol Pharm 14: 2624-2628
MeSH Terms: Antineoplastic Agents, Cell Survival, Concanavalin A, Doxorubicin, Drug Carriers, Hep G2 Cells, Humans, Hydrogen-Ion Concentration, Nanoparticles, Polyethylene Glycols, Polyethyleneimine, Polymers
Show Abstract · Added November 7, 2019
Nanogels with a biomolecular coating (biocoating) were shown to be capable of triggered delivery of anticancer drug Doxorubicin. The biocoating was formed utilizing binding between glycogen and the tetra-functional lectin Concanavalin A, which can be triggered to disassemble (and release) upon exposure to glucose and changes in solution pH. We also show the nanogel's thermoresponsivity can be used to accelerate Doxorubicin release. Moreover, we showed that transferrin immobilized on the nanogel surface could accelerate nanogel uptake by cancer cells. In these experiments, we showed that Doxorubicin was able to be released to the nucleus of human liver cancer cell line (HepG2) within 3 h. Doxorubicin-loaded nanogels exhibit a strong growth inhibition ability toward HepG2. This investigation showcases how nanogel design and chemistry can be tuned to achieve useful biomedical applications.
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Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.
Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, Chen X, Kirkbride KC, Doundoulakis T, Guerra ML, Zaias J, Fei DL, Rodriguez-Blanco J, Thorne C, Wang Z, Jin K, Nguyen DM, Sands LR, Marchetti F, Abreu MT, Cobb MH, Capobianco AJ, Lee E, Robbins DJ
(2017) Sci Signal 10:
MeSH Terms: Animals, Antineoplastic Agents, Benzoates, Casein Kinase Ialpha, Enzyme Activation, Enzyme Activators, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasms, Organ Culture Techniques, Phosphorylation, Pyrvinium Compounds, Signal Transduction, Surface Plasmon Resonance, Wnt Proteins, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, Xenopus laevis
Show Abstract · Added July 18, 2017
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms
Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity.
Wang J, Mouradov D, Wang X, Jorissen RN, Chambers MC, Zimmerman LJ, Vasaikar S, Love CG, Li S, Lowes K, Leuchowius KJ, Jousset H, Weinstock J, Yau C, Mariadason J, Shi Z, Ban Y, Chen X, Coffey RJC, Slebos RJC, Burgess AW, Liebler DC, Zhang B, Sieber OM
(2017) Gastroenterology 153: 1082-1095
MeSH Terms: Antineoplastic Agents, Biomarkers, Tumor, Cell Line, Tumor, Chromatography, Liquid, Colorectal Neoplasms, Databases, Protein, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Mutation, Neoplasm Proteins, Patient Selection, Polymorphism, Single Nucleotide, Precision Medicine, Proteome, Proteomics, Signal Transduction, Stromal Cells, Tandem Mass Spectrometry, Transcriptome, Tumor Microenvironment
Show Abstract · Added July 17, 2017
BACKGROUND AND AIMS - Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses.
METHODS - Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data.
RESULTS - Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post-transcriptional regulation were recapitulated in cell lines. The 5 proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling, and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses.
CONCLUSIONS - Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.
Kasper S, Reis H, Ziegler S, Nothdurft S, Mueller A, Goetz M, Wiesweg M, Phasue J, Ting S, Wieczorek S, Even A, Worm K, Pogorzelski M, Breitenbuecher S, Meiler J, Paul A, Trarbach T, Schmid KW, Breitenbuecher F, Schuler M
(2017) Oncotarget 8: 45898-45917
MeSH Terms: Antineoplastic Agents, Immunological, Apoptosis, Biomarkers, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, ErbB Receptors, Exons, Genes, ras, Humans, Mitogen-Activated Protein Kinases, Mutation, Odds Ratio, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Signal Transduction
Show Abstract · Added March 17, 2018
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.
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17 MeSH Terms
Epidermal growth factor receptor inhibition downregulates -induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.
Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM, Gobert AP, Wilson KT
(2018) Gut 67: 1247-1260
MeSH Terms: Animals, Antineoplastic Agents, Cell Culture Techniques, Epithelial Cells, ErbB Receptors, Gastritis, Gefitinib, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Quinazolines, Stomach Neoplasms
Show Abstract · Added June 29, 2017
OBJECTIVE - Gastric cancer is the third leading cause of cancer death worldwide and infection by is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.
DESIGN - We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of ( mice) were also used.
RESULTS - In C57BL/6 mice, gefitinib decreased and expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected versus control mice. In -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked ri-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from versus mice. Epithelial EGFR activation persisted in humans and mice after eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.
CONCLUSIONS - These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in -infected individuals.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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14 MeSH Terms
A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG
(2017) Br J Haematol 178: 547-560
MeSH Terms: Antineoplastic Agents, Benchmarking, Bortezomib, Cardiovascular Diseases, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Dyspnea, Heart Failure, Humans, Multiple Myeloma, Proteasome Inhibitors, Retrospective Studies, Risk Factors
Show Abstract · Added December 2, 2017
This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3-4·0% in studies in relapsed/refractory MM and 1·2-4·7% in previously untreated MM (2·0-7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3-5·9% grade ≥2; 0·6-4·1% grade ≥3), IHD (1·2-2·9% all grades; 0·4-2·7% grade ≥3) and cardiac death (0-1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.
© 2017 John Wiley & Sons Ltd.
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13 MeSH Terms
Mathematical models of cell phenotype regulation and reprogramming: Make cancer cells sensitive again!
Wooten DJ, Quaranta V
(2017) Biochim Biophys Acta Rev Cancer 1867: 167-175
MeSH Terms: Adaptation, Physiological, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Transformation, Neoplastic, Cellular Reprogramming, Drug Resistance, Neoplasm, Epigenesis, Genetic, Evolution, Molecular, Gene Expression Regulation, Neoplastic, Genetic Fitness, Genetic Predisposition to Disease, Heredity, Humans, Models, Genetic, Mutation, Neoplasms, Pedigree, Phenotype, Signal Transduction, Time Factors
Show Abstract · Added May 5, 2017
A cell's phenotype is the observable actualization of complex interactions between its genome, epigenome, and local environment. While traditional views in cancer have held that cellular and tumor phenotypes are largely functions of genomic instability, increasing attention has recently been given to epigenetic and microenvironmental influences. Such non-genetic factors allow cancer cells to experience intrinsic diversity and plasticity, and at the tumor level can result in phenotypic heterogeneity and treatment evasion. In 2006, Takahashi and Yamanaka exploited the epigenome's plasticity by "reprogramming" differentiated cells into a pluripotent state by inducing expression of a cocktail of four transcription factors. Recent advances in cancer biology have shown not only that cellular reprogramming is possible for malignant cells, but it may provide a foundation for future therapies. Nevertheless, cell reprogramming experiments are frequently plagued by low efficiency, activation of aberrant transcriptional programs, instability, and often rely on expertise gathered from systems which may not translate directly to cancer. Here, we review a theoretical framework tracing back to Waddington's epigenetic landscape which may be used to derive quantitative and qualitative understanding of cellular reprogramming. Implications for tumor heterogeneity, evolution and adaptation are discussed in the context of designing new treatments to re-sensitize recalcitrant tumors. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.
Copyright © 2017. Published by Elsevier B.V.
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21 MeSH Terms
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer.
Li C, Singh B, Graves-Deal R, Ma H, Starchenko A, Fry WH, Lu Y, Wang Y, Bogatcheva G, Khan MP, Milne GL, Zhao S, Ayers GD, Li N, Hu H, Washington MK, Yeatman TJ, McDonald OG, Liu Q, Coffey RJ
(2017) Proc Natl Acad Sci U S A 114: E2852-E2861
MeSH Terms: Animals, Antineoplastic Agents, Immunological, Cell Culture Techniques, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms, Crizotinib, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Hydroxyprostaglandin Dehydrogenases, Mice, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyridines, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Tissue Array Analysis, Versicans, Xenograft Model Antitumor Assays
Show Abstract · Added May 3, 2017
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFR-neutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most up-regulated genes in CC was the tumor suppressor , and the most up-regulated gene in SC was () in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.
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22 MeSH Terms
Multilayer photodynamic therapy for highly effective and safe cancer treatment.
Yang L, Zhang S, Ling X, Shao P, Jia N, Bai M
(2017) Acta Biomater 54: 271-280
MeSH Terms: Animals, Antineoplastic Agents, Breast Neoplasms, Cell Line, Tumor, Drug Delivery Systems, Female, Humans, Mice, Mice, Nude, Photochemotherapy, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes. Instead, significantly improved outcomes likely require synergistic therapies that target various cellular pathways. In this study, we target two proteins upregulated in cancers: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the CBR-targeted PS, IR700DX-mbc94, triggered necrotic cell death upon light irradiation, whereas PDT with the TSPO-targeted IR700DX-6T agent led to apoptotic cell death. Both PSs significantly inhibited tumor growth in vivo in a target-specific manner. As expected, the combined CBR- and TSPO-PDT resulted in enhanced cell killing efficacy and tumor inhibition with lower drug dose. The median survival time of animals with multilayer PDT treatment was extended by as much as 2.8-fold over single PDT treatment. Overall, multilayer PDT provides new opportunities to treat cancers with high efficacy and low side effects.
STATEMENT OF SIGNIFICANCE - Photodynamic therapy (PDT) is increasingly used as a minimally invasive, controllable and effective therapeutic procedure for cancer treatment. However, complete eradication of tumor cells by PDT alone remains challenging. In this study, we investigate the potential of multilayer PDT in cancer treatment with high efficacy and low side effects. Through PDT targeting two cancer biomarkers located at distinct subcellular localizations, remarkable synergistic effects in cancer cell killing and tumor inhibition were observed in both in vitro and in vivo experiments. This strategy may be widely applied to treat various cancer types by using strategically designed PDT photosensitizers that target corresponding upregulated receptors at tactical subcellular localization.
Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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