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Thouverey C, Apostolides P, Brun J, Caverzasio J, Ferrari S. Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells. JCI Insight 2024; 9:e176558. [PMID: 38713511 PMCID: PMC11141910 DOI: 10.1172/jci.insight.176558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 04/17/2024] [Indexed: 05/09/2024] Open
Abstract
While sclerostin-neutralizing antibodies (Scl-Abs) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Abs control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anticatabolic effect of Scl-Abs could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effects on M-CSF secretion and osteoclast activity in mice. Indeed, sclerostin coactivates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs in preosteoblasts. In turn, Scl-Ab prevents sclerostin-mediated coactivation of PDGFR signaling and consequent M-CSF upregulation in preosteoblast cultures, thereby inhibiting osteoclast activity in preosteoblast/osteoclast coculture assays. These results provide a potential mechanism explaining the dissociation between anabolic and antiresorptive effects of long-term Scl-Ab.
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Oliveira RFD, Stoltz IR, Gonçalves PG, Echevarria A, Taborda L, Lepinsk Lopes RH, Pereira LF, Elifio-Esposito S. Evaluation of the antitumoral effects of the mesoionic compound MI-D: Implications for endothelial cells viability and angiogenesis inhibition. Chem Biol Interact 2024; 387:110796. [PMID: 37951333 DOI: 10.1016/j.cbi.2023.110796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/19/2023] [Accepted: 11/03/2023] [Indexed: 11/13/2023]
Abstract
Angiogenesis is considered one of the hallmarks of cancer, assisting tumor progression and metastasis. The mesoionic compound, MI-D, can induce cell death and provoke cytoskeletal and metabolic changes in cancer cells. Using in vitro and in vivo models, this study aimed to evaluate the effects of MI-D on the viability of human endothelial cells (EC) and its ability to inhibit tumor-induced angiogenesis induced by tumoral cells. For in vitro analysis, colon carcinoma (HT29) and endothelial (EA.hy926) cells were used as the tumoral and angiogenesis models, respectively. To evaluate cytotoxicity, methylene blue viability stain and annexin-V/7AAD tests were performed with both cell types. For the angiogenesis experiments, scratch wound healing and capillary tube-like formation assays were performed with the EC. The in vivo tests were performed with the chorioallantoic membrane (HET-CAM) methodology, wherein gelatin sponge implants containing MI-D (5, 25, and 50 μM), HT29 cells, or both were grafted in the CAM. Our data showed that MI-D induced apoptosis in both endothelial and colon carcinoma cells, with a strong cytotoxic effect on the tumoral lineage. The drug inhibited the EC's migration and capillary-like structure formation in vitro. In the HET-CAM assays, MI-D reduced the number of blood vessels in the membrane when grafted alone and accompanied by tumor cells. In this study, MI-D interfered in important steps of angiogenesis, such as maintenance of endothelial cell viability, migration, formation of capillary-like structures, as well tumor-induced neovascularization, reinforcing the hypothesis that MI-D might act as an inhibitor of angiogenesis, and a potential antitumor agent.
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Affiliation(s)
- Ronaldo Figueira de Oliveira
- Post Graduate Program in Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil; School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | - Ian Rodrigo Stoltz
- School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | - Paola Gyuliane Gonçalves
- School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | - Aurea Echevarria
- Institute of Chemistry, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil
| | - Leandro Taborda
- School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | | | - Luiz Fernando Pereira
- School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil
| | - Selene Elifio-Esposito
- Post Graduate Program in Health Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil.
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Assi A, Farhat M, Hachem MCR, Zalaquett Z, Aoun M, Daher M, Sebaaly A, Kourie HR. Tyrosine kinase inhibitors in osteosarcoma: Adapting treatment strategiesa. J Bone Oncol 2023; 43:100511. [PMID: 38058514 PMCID: PMC10696463 DOI: 10.1016/j.jbo.2023.100511] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/19/2023] [Accepted: 11/01/2023] [Indexed: 12/08/2023] Open
Abstract
Osteosarcoma (OS) is an aggressive primary bone malignancy that metastasizes rapidly. The standard of care has changed little over the previous four decades, and survival rates have plateaued. In this context, tyrosine kinase inhibitors (TKIs) emerge as potential treatments. A literature search was conducted to collect data related to receptor tyrosine kinase genetic alterations and expression in OS specimens. Gene amplification and protein expression of these receptors were linked to prognosis and tumor behavior. Relevant TKIs were evaluated as monotherapies and as parts of combination therapies. Certain TKIs, such as apatinib, regorafenib, and cabozantinib, present a potential therapeutic avenue for OS patients, especially when combined with chemotherapy. Producing long-lasting responses and enhancing quality of life remain key goals in OS treatment. To this effect, optimizing the use of TKIs by identifying biomarkers predictive of response and assessing promising TKIs in larger-scale trials to validate the efficacy and safety outcomes relative to these drugs reported in phase II clinical trials. To this effect, it is necessary to identify biomarkers predictive of response to TKIs in larger-scale trials and to validate the efficacy and safety of these drugs reported in phase II clinical trials.
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Affiliation(s)
- Ahmad Assi
- Hematology-Oncology Department, Hotel Dieu de France, Beirut, Lebanon
| | - Mohamad Farhat
- Hematology-Oncology Department, Hotel Dieu de France, Beirut, Lebanon
| | | | - Ziad Zalaquett
- Hematology-Oncology Department, Hotel Dieu de France, Beirut, Lebanon
| | - Marven Aoun
- Orthopedics Department, Hotel Dieu de France, Beirut, Lebanon
| | - Mohammad Daher
- Orthopedics Department, Hotel Dieu de France, Beirut, Lebanon
- Orthopedics Department, Brown University, Providence, RI, USA
| | - Amer Sebaaly
- Orthopedics Department, Hotel Dieu de France, Beirut, Lebanon
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Romano F, Di Porzio A, Iaccarino N, Riccardi G, Di Lorenzo R, Laneri S, Pagano B, Amato J, Randazzo A. G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting. Expert Opin Ther Pat 2023; 33:745-773. [PMID: 37855085 DOI: 10.1080/13543776.2023.2271168] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023]
Abstract
INTRODUCTION Guanine-rich DNA sequences can fold into four-stranded noncanonical secondary structures called G-quadruplexes (G4s) which are widely distributed in functional regions of the human genome, such as telomeres and gene promoter regions. Compelling evidence suggests their involvement in key genome functions such as gene expression and genome stability. Notably, the abundance of G4-forming sequences near transcription start sites suggests their potential involvement in regulating oncogenes. AREAS COVERED This review provides an overview of current knowledge on G4s in human oncogene promoters. The most representative G4-binding ligands have also been documented. The objective of this work is to present a comprehensive overview of the most promising targets for the development of novel and highly specific anticancer drugs capable of selectively impacting the expression of individual or a limited number of genes. EXPERT OPINION Modulation of G4 formation by specific ligands has been proposed as a powerful new tool to treat cancer through the control of oncogene expression. Actually, most of G4-binding small molecules seem to simultaneously target a range of gene promoter G4s, potentially influencing several critical driver genes in cancer, thus producing significant therapeutic benefits.
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Affiliation(s)
- Francesca Romano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Anna Di Porzio
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Nunzia Iaccarino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | | | - Sonia Laneri
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Bruno Pagano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Jussara Amato
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Antonio Randazzo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
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Saltarella I, Altamura C, Campanale C, Laghetti P, Vacca A, Frassanito MA, Desaphy JF. Anti-Angiogenic Activity of Drugs in Multiple Myeloma. Cancers (Basel) 2023; 15:cancers15071990. [PMID: 37046651 PMCID: PMC10093708 DOI: 10.3390/cancers15071990] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/20/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients’ prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting the importance of inhibiting angiogenesis from potentiating the antimyeloma activity. Here, we review the most important anti-angiogenic therapies used for the management of MM patients with a particular focus on their pharmacological profile and on their anti-angiogenic effect in vitro and in vivo. Despite the promising perspective, the direct targeting of angiogenic cytokines/receptors did not show a great efficacy in MM patients, suggesting the need to a deeper knowledge of the BM angiogenic niche for the design of novel multi-targeting anti-angiogenic therapies.
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Affiliation(s)
- Ilaria Saltarella
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Concetta Altamura
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Carmen Campanale
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Paola Laghetti
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Clinical Pathology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Jean-François Desaphy
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy
- Correspondence:
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Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma. Int J Mol Sci 2022; 23:ijms232416162. [PMID: 36555805 PMCID: PMC9786043 DOI: 10.3390/ijms232416162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/03/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Endoplasmic reticulum stress activates inositol-requiring enzyme 1α (IRE1α) and protein kinase, R-like endoplasmic reticulum kinase (PERK), the two principal regulators of the unfolded protein response (UPR). In multiple myeloma, adaptive IRE1α signaling is predominantly activated and regulates cell fate along with PERK. Recently, we demonstrated that GNF-2, an allosteric c-Abl inhibitor, rheostatically enhanced IRE1α activity and induced apoptosis through c-Abl conformational changes in pancreatic β cells. Herein, we analyzed whether the pharmacological modulation of c-Abl conformation resulted in anti-myeloma effects. First, we investigated the effects of GNF-2 on IRE1α activity and cell fate, followed by an investigation of the anti-myeloma effects of asciminib, a new allosteric c-Abl inhibitor. Finally, we performed RNA sequencing to characterize the signaling profiles of asciminib. We observed that both GNF-2 and asciminib decreased cell viability and induced XBP1 mRNA splicing in primary human myeloma cells and myeloma cell lines. RNA sequencing identified the induction of UPR- and apoptosis-related genes by asciminib. Asciminib re-localized c-Abl to the endoplasmic reticulum, and its combination with a specific IRE1α inhibitor, KIRA8, enhanced cell death with the reciprocal induction of CHOP mRNA expression. Together, the allosteric inhibition of c-Abl-activated UPR with anti-myeloma effects; this could be a novel therapeutic target for multiple myeloma.
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Molecular Crosstalk between Chromatin Remodeling and Tumor Microenvironment in Multiple Myeloma. Curr Oncol 2022; 29:9535-9549. [PMID: 36547163 PMCID: PMC9777166 DOI: 10.3390/curroncol29120749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/28/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple myeloma (MM) is a complex disease driven by numerous genetic and epigenetic alterations that are acquired over time. Despite recent progress in the understanding of MM pathobiology and the availability of innovative drugs, which have pronounced clinical outcome, this malignancy eventually progresses to a drug-resistant lethal stage and, thus, novel therapeutic drugs/models always play an important role in effective management of MM. Modulation of tumor microenvironment is one of the hallmarks of cancer biology, including MM, which affects the myeloma genomic architecture and disease progression subtly through chromatin modifications. The bone marrow niche has a prime role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the ecosystem between multiple myeloma bone marrow microenvironment and chromatin remodeling. Extensive gene expression profile analysis has indeed provided the framework for new risk stratification of MM patients and identifying novel molecular targets and therapeutics. However, key tumor microenvironment factors/immune cells and their interactions with chromatin remodeling complex proteins that drive MM cell growth and progression remain grossly undefined.
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Melaccio A, Reale A, Saltarella I, Desantis V, Lamanuzzi A, Cicco S, Frassanito MA, Vacca A, Ria R. Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance. J Clin Med 2022; 11:jcm11216491. [PMID: 36362718 PMCID: PMC9658666 DOI: 10.3390/jcm11216491] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/23/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022] Open
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.
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Affiliation(s)
- Assunta Melaccio
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.M.); (R.R.); Tel.: +39-320-55-17-232 (A.M.)
| | - Antonia Reale
- Myeloma Research Group, Australian Centre for Blood Diseases, Central Clinical School, Monash University—Alfred Health, Melbourne 3004, Australia
| | - Ilaria Saltarella
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Vanessa Desantis
- Department of Biomedical Sciences and Human Oncology, Pharmacology Section, University of Bari Aldo Moro Medical School, 70124 Bari, Italy
| | - Aurelia Lamanuzzi
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Sebastiano Cicco
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Maria Antonia Frassanito
- General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
| | - Roberto Ria
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (A.M.); (R.R.); Tel.: +39-320-55-17-232 (A.M.)
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The serine protease matriptase inhibits migration and proliferation in multiple myeloma cells. Oncotarget 2022; 13:1175-1186. [PMID: 36268559 PMCID: PMC9584456 DOI: 10.18632/oncotarget.28300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Multiple myeloma (MM) is an incurable malignancy of plasma cells. The serine protease matriptase is frequently dysregulated in human carcinomas, which facilitates tumor progression and metastatic dissemination. The importance of matriptase in hematological malignancies is yet to be clarified. In this study, we aimed to characterize the role of matriptase in MM. MATERIALS AND METHODS mRNA expression of matriptase and its inhibitors hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2 was studied in primary MM cells from patient samples and human myeloma cell lines (HMCLs). We further investigated the effect of matriptase on migration and proliferation of myeloma cells in vitro. By use of the CoMMpass database, we assessed the clinical relevance of matriptase in MM patients. RESULTS Matriptase was expressed in 96% of patient samples and all HMCLs tested. Overexpression of matriptase in vitro reduced proliferation, and significantly decreased cytokine-induced migration. Conversely, matriptase knockdown significantly enhanced migration. Mechanistically, overexpression of matriptase inhibited activation of Src kinase. CONCLUSIONS Our findings may suggest a novel role of matriptase as a tumor suppressor in MM pathogenesis.
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Directly targeting c-Myc contributes to the anti-multiple myeloma effect of anlotinib. Cell Death Dis 2021; 12:396. [PMID: 33854043 PMCID: PMC8046985 DOI: 10.1038/s41419-021-03685-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 03/20/2021] [Accepted: 03/25/2021] [Indexed: 12/21/2022]
Abstract
Despite the significant advances in the treatment of multiple myeloma (MM), this disease is still considered incurable because of relapse and chemotherapy resistance, underscoring the need to seek novel therapies with different mechanisms. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging antitumor activity in several preclinical and clinical trials, but its effect on MM has not been studied yet. In this study, we found that anlotinib exhibits encouraging cytotoxicity in MM cells, overcomes the protective effect of the bone marrow microenvironment and suppresses tumor growth in the MM mouse xenograft model. We further examined the underlying molecular mechanism and found that anlotinib provokes cell cycle arrest, induces apoptosis and inhibits multiple signaling pathways. Importantly, we identify c-Myc as a novel direct target of anlotinib. The enhanced ubiquitin proteasomal degradation of c-Myc contributes to the cell apoptosis induced by anlotinib. In addition, anlotinib also displays strong cytotoxicity against bortezomib-resistant MM cells. Our study demonstrates the extraordinary anti-MM effect of anlotinib both in vitro and in vivo, which provides solid evidence and a promising rationale for future clinical application of anlotinib in the treatment of human MM.
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Wang H, Liu H, Sun C, Liu C, Jiang T, Yin Y, Xu A, Pang Z, Zhang B, Hu Y. Nanoparticles Dual Targeting Both Myeloma Cells and Cancer-Associated Fibroblasts Simultaneously to Improve Multiple Myeloma Treatment. Pharmaceutics 2021; 13:pharmaceutics13020274. [PMID: 33670464 PMCID: PMC7922689 DOI: 10.3390/pharmaceutics13020274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 01/24/2021] [Accepted: 02/10/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) and myeloma cells could mutually drive myeloma progression, indicating that drug delivery to kill both CAFs and myeloma cells simultaneously could achieve better therapeutic benefits than to kill each cell type alone. Here, we designed a dual-targeting drug delivery system by conjugating paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles (NPs) with a cyclic peptide (CNPs-PTX) with a special affinity with platelet-derived growth factor/platelet-derived growth factor receptor (PDGFR-β) overexpressed on both CAFs and myeloma cells. Cellular uptake experiments revealed that the cyclic peptide modification on CNPs could significantly enhance CNPs uptake by both CAFs and myeloma cells compared with unmodified NPs. Cytotoxicity tests showed that CNPs-PTX was more toxic to both CAFs and myeloma cells compared with its counterpart PTX-loaded conventional NPs (NPs-PTX). In vivo imaging and biodistribution experiments showed that CNPs could abundantly accumulate in tumors and were highly co-localized with CAFs and myeloma cells. The in vivo anti-tumor experiments confirmed that the anti-myeloma efficacy of CNPs-PTX was significantly stronger than that of NPs-PTX and free drugs. In summary, it is the first time that a dual-targeting strategy was utilized in the field of myeloma treatment through targeting both CAFs and myeloma cells simultaneously, which harbors a high potential of clinical translation for myeloma treatment.
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Affiliation(s)
- Honglan Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Huiwen Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Chunying Liu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China;
| | - Ting Jiang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Yanxue Yin
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Aoshuang Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
| | - Zhiqing Pang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China;
- Correspondence: (Z.P.); (B.Z.); (Y.H.); Tel.: +86-21-51980069 (Z.P.); +86-27-85726007 (B.Z.); +86-27-85726335 (Y.H.); Fax: +86-21-51980069 (Z.P.); +86-27-85726387 (B.Z.); +86-27-85776343 (Y.H.)
| | - Bo Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
- Correspondence: (Z.P.); (B.Z.); (Y.H.); Tel.: +86-21-51980069 (Z.P.); +86-27-85726007 (B.Z.); +86-27-85726335 (Y.H.); Fax: +86-21-51980069 (Z.P.); +86-27-85726387 (B.Z.); +86-27-85776343 (Y.H.)
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430022, China; (H.W.); (H.L.); (C.S.); (T.J.); (Y.Y.); (A.X.)
- Correspondence: (Z.P.); (B.Z.); (Y.H.); Tel.: +86-21-51980069 (Z.P.); +86-27-85726007 (B.Z.); +86-27-85726335 (Y.H.); Fax: +86-21-51980069 (Z.P.); +86-27-85726387 (B.Z.); +86-27-85776343 (Y.H.)
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Brun J, Andreasen CM, Ejersted C, Andersen TL, Caverzasio J, Thouverey C. PDGF Receptor Signaling in Osteoblast Lineage Cells Controls Bone Resorption Through Upregulation of Csf1 Expression. J Bone Miner Res 2020; 35:2458-2469. [PMID: 32777109 DOI: 10.1002/jbmr.4150] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/25/2020] [Accepted: 07/29/2020] [Indexed: 12/15/2022]
Abstract
The physiological functions of platelet-derived growth factor receptors (PDGFRs) α and β in osteoblast biology and bone metabolism remain to be established. Here, we show that PDGFRA and PDGFRB genes are expressed by osteoblast-lineage canopy and reversal cells in close proximity to PDGFB-expressing osteoclasts within human trabecular bone remodeling units. We also report that, although removal of only one of the two PDGFRs in Osterix-positive cells does not affect bone phenotype, suppression of both PDGFRs in those osteoblast lineage cells increases trabecular bone volume in male mice as well as in female gonad-intact and ovariectomized mice. Furthermore, osteoblast lineage-specific suppression of PDGFRs reduces Csf1 expression, bone marrow level of macrophage colony-stimulating factor (M-CSF), number of osteoclasts, and, therefore, bone resorption, but does not change bone formation. Finally, abrogation of PDGFR signaling in osteoblasts blocks PDGF-induced ERK1/2-mediated Csf1 expression and M-CSF secretion in osteoblast cultures and calcitriol-mediated osteoclastogenesis in co-cultures. In conclusion, our results indicate that PDGFR signaling in osteoblast lineage cells controls bone resorption through ERK1/2-mediated Csf1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Julia Brun
- Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
| | - Christina Møller Andreasen
- Clinical Cell Biology, Pathology Research Unit, Odense University Hospital, Odense C, Denmark.,Department of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
| | - Charlotte Ejersted
- Department of Endocrinology, Odense University Hospital, Odense C, Denmark
| | - Thomas Levin Andersen
- Clinical Cell Biology, Pathology Research Unit, Odense University Hospital, Odense C, Denmark.,Department of Molecular Medicine, University of Southern Denmark, Odense C, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense C, Denmark
| | - Joseph Caverzasio
- Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
| | - Cyril Thouverey
- Service of Bone Diseases, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
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13
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Tabata M, Tsubaki M, Takeda T, Tateishi K, Maekawa S, Tsurushima K, Imano M, Satou T, Ishizaka T, Nishida S. Inhibition of HSP90 overcomes melphalan resistance through downregulation of Src in multiple myeloma cells. Clin Exp Med 2020; 20:63-71. [PMID: 31650359 DOI: 10.1007/s10238-019-00587-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/16/2019] [Indexed: 10/25/2022]
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy. In spite of the development of new therapeutic agents, MM remains incurable due to multidrug resistance (MDR) and the 5-year survival rate is approximately 50%. Thus, further study is needed to investigate the mechanism of MDR and improve MM prognosis. Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the stability of a number of client proteins, most of which are involved in tumor progression. Therefore, HSP90 inhibitors represent potential new therapeutic agents for cancer. Furthermore, inhibition of HSP90 leads to degradation of client proteins, overcoming acquired anti-cancer drug resistance. In this study, we assessed the role of HSP90 in MDR using established melphalan-resistant MM cells. We found that expression of HSP90 was higher in melphalan-resistant MM cells than in parent cells and that HSP90 inhibitors KW-2478 and NUV-AUY922 restored drug sensitivity to the level observed in parent cells. Activation of the unfolded protein response is a hallmark of MM, and expression of endoplasmic reticulum stress signaling molecules is reduced in melphalan-resistant cells; however, KW-2478 did not affect endoplasmic reticulum stress signaling. We demonstrated that treatment with KW-2478 decreased expression of Src, a client of HSP90, and suppressed the activity of ERK, Akt, and NF-κB. Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM.
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Affiliation(s)
- Mitsuki Tabata
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
| | - Masanobu Tsubaki
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
| | - Tomoya Takeda
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
| | - Keisuke Tateishi
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
| | - Saho Maekawa
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
| | - Katsumasa Tsurushima
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan
- Department of Pharmacy, Sakai City Medical Center, Sakai, Japan
| | - Motohiro Imano
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan
| | - Takao Satou
- Department of Pathology, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan
| | | | - Shozo Nishida
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Kowakae, Higashiōsaka, 577-8502, Japan.
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14
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Mai W, Chen M, Huang M, Zhong J, Chen J, Liu X, Deng J, Yang X, Ye W, Zhang R, Zhou Q, Zhang D. Targeting platelet-derived growth factor receptor β inhibits the proliferation and motility of human pterygial fibroblasts. Expert Opin Ther Targets 2019; 23:805-817. [PMID: 31385548 DOI: 10.1080/14728222.2019.1653281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Background: Pterygium, a common eye disease with high postoperative recurrence, lacks effective therapeutic strategies. Therefore, it's urgent to identify specific targets to develop rationally targeted molecular drugs for the pterygial therapy. Methods: The cell proliferation and motility were studied in both the primary human pterygial fibroblasts (hPFs) and an ex vivo pterygium model. hPFs transfected with the pCMV3-PDGFRB plasmid, PDGFRB siRNA and CRISPR/Cas9 system were used to determine the role of PDGFR-β in pterygial fibroblasts functions. Western blotting, immunohistochemistry and immunofluorescence were performed to evaluate the expression of the key proteins. Results: PDGFR-β expression in the pterygial stroma and primary hPFs was significantly higher than that in the conjunctiva and human conjunctival fibroblasts. PDGF-BB promoted the proliferation, migration and invasion of hPFs, which can be significantly suppressed by sunitinib via inhibition of the PDGFR-β/extracellular signal-regulated kinase (ERK) pathway. In the ex vivo model, the knockout of PDGFRB and sunitinib treatment blocked the proliferation and motility of fibroblasts in the pterygial stroma via the suppression of PDGFR-β/ERK pathway. Conclusion: This study demonstrates that PDGFR-β may be a potential therapeutic target for pterygium, and inhibition of PDGFR-β by sunitinib is a promising and effective approach for pterygium treatment.
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Affiliation(s)
- Weiqian Mai
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
| | - Minfeng Chen
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
| | - Maohua Huang
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
| | - Jincheng Zhong
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
| | - Jian Chen
- Eye Institute, Jinan University , Guangzhou , China
| | - Xiaoyong Liu
- The First Affiliated Hospital of Jinan University , Guangzhou , China
| | - Juan Deng
- The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
| | - Xiaoxi Yang
- The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
| | - Wencai Ye
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
| | - Rijia Zhang
- The First Affiliated Hospital of Jinan University , Guangzhou , China
| | - Qing Zhou
- The First Affiliated Hospital of Jinan University , Guangzhou , China
| | - Dongmei Zhang
- College of Pharmacy, Jinan University , Guangzhou , China.,Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University , Guangzhou , China
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15
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D'Oronzo S, Coleman R, Brown J, Silvestris F. Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management. J Bone Oncol 2019; 15:004-4. [PMID: 30937279 PMCID: PMC6429006 DOI: 10.1016/j.jbo.2018.10.004] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/22/2018] [Accepted: 10/28/2018] [Indexed: 12/17/2022] Open
Abstract
Bone metastases (BM) are a common complication of cancer, whose management often requires a multidisciplinary approach. Despite the recent therapeutic advances, patients with BM may still experience skeletal-related events and symptomatic skeletal events, with detrimental impact on quality of life and survival. A deeper knowledge of the mechanisms underlying the onset of lytic and sclerotic BM has been acquired in the last decades, leading to the development of bone-targeting agents (BTA), mainly represented by anti-resorptive drugs and bone-seeking radiopharmaceuticals. Recent pre-clinical and clinical studies have showed promising effects of novel agents, whose safety and efficacy need to be confirmed by prospective clinical trials. Among BTA, adjuvant bisphosphonates have also been shown to reduce the risk of BM in selected breast cancer patients, but failed to reduce the incidence of BM from lung and prostate cancer. Moreover, adjuvant denosumab did not improve BM free survival in patients with breast cancer, suggesting the need for further investigation to clarify BTA role in early-stage malignancies. The aim of this review is to describe BM pathogenesis and current treatment options in different clinical settings, as well as to explore the mechanism of action of novel potential therapeutic agents for which further investigation is needed.
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Key Words
- ActRIIA, activin-A type IIA receptor
- BC, breast cancer
- BM, bone metastases
- BMD, bone mineral density
- BMPs, bone morphogenetic proteins
- BMSC, bone marrow stromal cells
- BPs, bisphosphonates
- BTA, bone targeting agents
- BTM, bone turnover markers
- Bone metastases
- Bone targeting agents
- CCR, chemokine-receptor
- CRPC, castration-resistant PC
- CXCL-12, C–X–C motif chemokine-ligand-12
- CXCR-4, chemokine-receptor-4
- DFS, disease-free survival
- DKK1, dickkopf1
- EBC, early BC
- ECM, extracellular matrix
- ET-1, endothelin-1
- FDA, food and drug administration
- FGF, fibroblast growth factor
- GAS6, growth-arrest specific-6
- GFs, growth factors
- GnRH, gonadotropin-releasing hormone
- HER-2, human epidermal growth factor receptor 2
- HR, hormone receptor
- IL, interleukin
- LC, lung cancer
- MAPK, mitogen-activated protein kinase
- MCSF, macrophage colony-stimulating factor
- MCSFR, MCSF receptor
- MIP-1α, macrophage inflammatory protein-1 alpha
- MM, multiple myeloma
- MPC, malignant plasma cells
- N-BPs, nitrogen-containing BPs
- NF-κB, nuclear factor-κB
- ONJ, osteonecrosis of the jaw
- OS, overall survival
- Osteotropic tumors
- PC, prostate cancer
- PDGF, platelet-derived growth factor
- PFS, progression-free survival
- PIs, proteasome inhibitors
- PSA, prostate specific antigen
- PTH, parathyroid hormone
- PTH-rP, PTH related protein
- QoL, quality of life
- RANK-L, receptor activator of NF-κB ligand
- RT, radiation therapy
- SREs, skeletal-related events
- SSEs, symptomatic skeletal events
- Skeletal related events
- TGF-β, transforming growth factor β
- TK, tyrosine kinase
- TKIs, TK inhibitors
- TNF, tumornecrosis factor
- VEGF, vascular endothelial growth factor
- VEGFR, VEGF receptor
- mTOR, mammalian target of rapamycin
- non-N-BPs, non-nitrogen containing BPs
- v-ATPase, vacuolar-type H+ ATPase
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Affiliation(s)
- Stella D'Oronzo
- Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, P.za Giulio Cesare, 11, 70124 Bari, Italy
| | - Robert Coleman
- Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Whitham Rd, Sheffield S10 2SJ, England, UK
| | - Janet Brown
- Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Whitham Rd, Sheffield S10 2SJ, England, UK
| | - Francesco Silvestris
- Medical Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, P.za Giulio Cesare, 11, 70124 Bari, Italy
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16
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Qu C, Zhang J, Zhang X, Du J, Su B, Li H. Value of combined detection of anti-nuclear antibody, anti-double-stranded DNA antibody and C3, C4 complements in the clinical diagnosis of systemic lupus erythematosus. Exp Ther Med 2018; 17:1390-1394. [PMID: 30680018 PMCID: PMC6327606 DOI: 10.3892/etm.2018.7072] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 11/19/2018] [Indexed: 01/22/2023] Open
Abstract
Combined detection of antinuclear antibody (ANA), anti-double-stranded DNA (ds-DNA) antibody and complements C3 and C4 in the diagnosis of systemic lupus erythematosus (SLE) was analyzed. One hundred and ninety-four patients with SLE admitted to Yantaishan Hospital of Yantai from January 2012 to December 2017 were selected as SLE group. A total of 106 patients with non-SLE rheumatic disease were selected as disease control group and 120 healthy subjects as healthy control group. The ANA and anti-ds-DNA antibodies were detected by ELISA and complement C3 and C4 were detected by rate nephelometry. The sensitivity and specificity of these four factors were also analyzed for the diagnosis of SLE. The sensitivity and specificity of ANA in diagnosing SLE were 91.75 and 79.65%, respectively; of anti-ds-DNA antibody were 67.01 and 98.23%, respectively; of complement C3 were 87.11 and 82.74%, respectively; and of complement C4 were 88.66 and 77.43%, respectively. The sensitivity and specificity of ANA and anti-ds-DNA antibody in the diagnosis of SLE were 95.36 and 96.90%, respectively; of C3 and C4 were 92.78 and 79.20%, respectively; and the sensitivity and specificity of the combination of all four indicators were 97.42 and 80.97%, respectively. The combined diagnosis of SLE with ANA, anti-ds-DNA antibody, complement C3 and C4 can play a complementary role in the diagnosis and treatment of SLE patients, and it is of great significance to the diagnosis and treatment planning of SLE patients.
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Affiliation(s)
- Changhua Qu
- Department of Clinical Laboratory, Yantaishan Hospital of Yantai, Yantai, Shandong 264000, P.R. China
| | - Juan Zhang
- Outpatient Department, Yantai Yeda Hospital, Yantai, Shandong 264000, P.R. China
| | - Xiumei Zhang
- Department of Internal Medicine, The People's Hospital of Zhangqiu Area, Zhangqiu, Shandong 250200, P.R. China
| | - Jiexin Du
- Department of Neurology, The People's Hospital of Zhangqiu Area, Zhangqiu, Shandong 250200, P.R. China
| | - Baifang Su
- Department of Science and Education, Jinan Zhangqiu District Hospital of TCM, Zhangqiu, Shandong 250200, P.R. China
| | - Hong Li
- Department of Clinical Laboratory, The Fifth People's Hospital of Jinan, Jinan, Shandong 250022, P.R. China
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17
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Zarfati M, Avivi I, Brenner B, Katz T, Aharon A. Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis. Angiogenesis 2018; 22:185-196. [PMID: 30386953 DOI: 10.1007/s10456-018-9649-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
Abstract
Bone marrow microenvironment is known to support angiogenesis, thus contributing to progression of multiple myeloma (MM). Bortezomib, a proteasome inhibitor (PI) widely used in MM treatment, has anti-angiogenic activity. Extracellular vesicles (EVs), shedding from cell surface, serve as mediators in cell-to-cell communication. We have hypothesized that MM cells (MMCs) treated with bortezomib generate EVs that could diminish angiogenesis, thus limiting MM progression. In the present study, EVs were obtained from MMCs (RPMI-8226), untreated (naïve) or pre-treated with bortezomib. EVs were outlined using NanoSight, FACS, protein arrays and proteasome activity assays. The impact of MMC-EVs on endothelial cell (EC) functions was assessed, employing XTT assay, Boyden chamber and Western blot. A high apoptosis level (annexin V binding 70.25 ± 16.37%) was observed in MMCs following exposure to bortezomib. Compared to naïve EVs, a large proportion of bortezomib-induced EVs (Bi-EVs) were bigger in size (> 300 nm), with higher levels of annexin V binding (p = 0.0043).They also differed in content, presenting with increased levels of pro-inflammatory proteins, reduced levels of pro-angiogenic growth factors (VEGFA, PDGF-BB, angiogenin), and displayed lower proteasome activity. Naïve EVs were found to promote EC migration and proliferation via ERK1/2 and JNK1/2/3 phosphorylation, whereas Bi-EVs inhibited these functions. Moreover, Bi-EVs appeared to reduce EC proteasome activity. EVs released from apoptotic MMCs following treatment with bortezomib can promote angiogenesis suppression by decreasing proliferation and migration of EC. These activities are found to be mediated by specific signal transduction pathways.
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Affiliation(s)
- Moran Zarfati
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
| | - Irit Avivi
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Benjamin Brenner
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Tami Katz
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel
| | - Anat Aharon
- Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. .,Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 7, Ha'Aliya St., Haifa, 3109601, Israel.
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18
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Mashimo K, Tsubaki M, Takeda T, Asano R, Jinushi M, Imano M, Satou T, Sakaguchi K, Nishida S. RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells. Clin Exp Med 2018; 19:133-141. [DOI: 10.1007/s10238-018-0531-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/27/2018] [Indexed: 12/23/2022]
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19
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Ribatti D, Vacca A. New Insights in Anti-Angiogenesis in Multiple Myeloma. Int J Mol Sci 2018; 19:ijms19072031. [PMID: 30002349 PMCID: PMC6073492 DOI: 10.3390/ijms19072031] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 12/12/2022] Open
Abstract
Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and involves direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment. This article summarizes the more recent literature data concerning the employment of anti-angiogenic therapeutic agents actually used in preclinical models and clinical settings for the treatment of multiple myeloma.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari 70124, Italy.
| | - Angelo Vacca
- Department of Biomedical Sciences, and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari 70124, Italy.
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20
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Gao Q, Yellapantula V, Fenelus M, Pichardo J, Wang L, Landgren O, Dogan A, Roshal M. Tumor suppressor CD99 is downregulated in plasma cell neoplasms lacking CCND1 translocation and distinguishes neoplastic from normal plasma cells and B-cell lymphomas with plasmacytic differentiation from primary plasma cell neoplasms. Mod Pathol 2018; 31:881-889. [PMID: 29403080 PMCID: PMC5998376 DOI: 10.1038/s41379-018-0011-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 12/06/2017] [Indexed: 02/07/2023]
Abstract
CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B-cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; and (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood, and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, 8 out of 56 samples (14%) showed visibly (>10-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81, and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with cyclin D1 translocation in myeloma (p < 0.05). B-cell lymphomas with plasma cell component could be distinguished from myeloma by CD99 expression. In summary, we established that tumor suppressor CD99 is markedly downregulated in multiple myeloma. The loss is highly specific for identification of abnormal cells in primary plasma cell neoplasms, and can be exploited for diagnostic purposes. The role of CD99 in myeloma pathogenesis requires further investigation.
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Affiliation(s)
- Qi Gao
- Hematopathology Service, Memorial Sloan Kettering Cancer Center
| | - Venkata Yellapantula
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
| | - Maly Fenelus
- Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center
| | - Janine Pichardo
- Hematopathology Service, Memorial Sloan Kettering Cancer Center
| | - Lu Wang
- Department of Pathology, Memorial Sloan Kettering Cancer Center
| | - Ola Landgren
- Myeloma Service, Memorial Sloan Kettering Cancer Center
| | - Ahmet Dogan
- Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Mikhail Roshal
- Hematopathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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21
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Manni S, Carrino M, Semenzato G, Piazza F. Old and Young Actors Playing Novel Roles in the Drama of Multiple Myeloma Bone Marrow Microenvironment Dependent Drug Resistance. Int J Mol Sci 2018; 19:ijms19051512. [PMID: 29783691 PMCID: PMC5983700 DOI: 10.3390/ijms19051512] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 05/15/2018] [Accepted: 05/15/2018] [Indexed: 12/19/2022] Open
Abstract
Multiple myeloma (MM) is the second most frequent hematologic cancer. In addition to the deleterious effects of neoplastic plasma cell growth and spreading during the disease evolution, this tumor is characterized by the serious pathological consequences due to the massive secretion of monoclonal immunoglobulins and by the derangement of bone physiology with progressive weakening of the skeleton. Despite significant progresses having been made in the last two decades in the therapeutic management of this plasma cell tumor, MM remains invariably lethal, due to its extremely complex genetic architecture and to the constant protection it receives from the tumor niche, which is represented by the bone marrow microenvironment. While it is predictable that the discovery of novel therapies against the first of these two pathobiological features will take a longer time, the identification of the cellular and molecular mechanisms underlying the pro-growth effects of the myeloma milieu is a task that could lead to the development of novel treatments in a shorter timeframe. In this regard, aside from known “old” determinants of the cross-talk between bone marrow and MM cells, “young” cellular and molecular factors are now emerging, taking the scene of this complex neoplastic setting. In this review we aimed at giving insights on the latest evidence of potentially-targetable modes that MM cells exploit to increase fitness and gain a survival advantage. The benefits coming from the derangements of stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs are examples of such methods that MM cells utilize to escape cell death, but that hopefully will offer novel targets for the ever-increasing anti-MM therapeutic armamentarium.
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Affiliation(s)
- Sabrina Manni
- Department of Medicine, Hematology Section, University of Padova, Via N.Giustiniani 2, 35128 Padova, Italy.
- Venetian Institute of Molecular Medicine, Via G.Orus 2, 35129 Padova, Italy.
| | - Marilena Carrino
- Department of Medicine, Hematology Section, University of Padova, Via N.Giustiniani 2, 35128 Padova, Italy.
- Venetian Institute of Molecular Medicine, Via G.Orus 2, 35129 Padova, Italy.
| | - Gianpietro Semenzato
- Department of Medicine, Hematology Section, University of Padova, Via N.Giustiniani 2, 35128 Padova, Italy.
- Venetian Institute of Molecular Medicine, Via G.Orus 2, 35129 Padova, Italy.
| | - Francesco Piazza
- Department of Medicine, Hematology Section, University of Padova, Via N.Giustiniani 2, 35128 Padova, Italy.
- Venetian Institute of Molecular Medicine, Via G.Orus 2, 35129 Padova, Italy.
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22
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Tan HY, Wang N, Lam W, Guo W, Feng Y, Cheng YC. Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol Cancer 2018; 17:43. [PMID: 29455663 PMCID: PMC5817793 DOI: 10.1186/s12943-018-0800-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 02/01/2018] [Indexed: 12/12/2022] Open
Abstract
Tumour microenvironment (TME) is a key determinant of tumour growth and metastasis. TME could be very different for each type and location of tumour and TME may change constantly during tumour growth. Multiple counterparts in surrounding microenvironment including mesenchymal-, hematopoietic-originated cells as well as non-cellular components affect TME. Thus, therapeutics that can disrupt the tumour-favouring microenvironment should be further explored for cancer therapy. Previous efforts in unravelling the dysregulated mechanisms of TME components has identified numerous protein tyrosine kinases, while its corresponding inhibitors have demonstrated potent modulatory effect on TME. Recent works have demonstrated that beyond the direct action on cancer cells, tyrosine kinase inhibitors (TKIs) have been implicated in inactivation or normalization of dysregulated TME components leading to cancer regression. Either through re-sensitizing the tumour cells or reversing the immunological tolerance microenvironment, the emergence of these TME modulatory mechanism of TKIs supports the combinatory use of TKIs with current chemotherapy or immunotherapy for cancer therapy. Therefore, an appropriate understanding on TME modulation by TKIs may offer another mode of action of TKIs for cancer treatment. This review highlights mode of kinase activation or paracrine ligand production from TME components and summarises the findings on the potential use of various TKIs on regulating TME components. At last, the combination use of current TKIs with immunotherapy in the perspectives of efficacy and safety are discussed.
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Affiliation(s)
- Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Wing Lam
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA
| | - Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China.
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
| | - Yung-Chi Cheng
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA.
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23
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Abramson HN. Kinase inhibitors as potential agents in the treatment of multiple myeloma. Oncotarget 2018; 7:81926-81968. [PMID: 27655636 PMCID: PMC5348443 DOI: 10.18632/oncotarget.10745] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 06/30/2016] [Indexed: 12/13/2022] Open
Abstract
Recent years have witnessed a dramatic increase in the number of therapeutic options available for the treatment of multiple myeloma (MM) - from immunomodulating agents to proteasome inhibitors to histone deacetylase (HDAC) inhibitors and, most recently, monoclonal antibodies. Used in conjunction with autologous hematopoietic stem cell transplantation, these modalities have nearly doubled the disease's five-year survival rate over the last three decades to about 50%. In spite of these advances, MM still is considered incurable as resistance and relapse are common. While small molecule protein kinase inhibitors have made inroads in the therapy of a number of cancers, to date their application to MM has been less than successful. Focusing on MM, this review examines the roles played by a number of kinases in driving the malignant state and the rationale for target development in the design of a number of kinase inhibitors that have demonstrated anti-myeloma activity in both in vitro and in vivo xenograph models, as well as those that have entered clinical trials. Among the targets and their inhibitors examined are receptor and non-receptor tyrosine kinases, cell cycle control kinases, the PI3K/AKT/mTOR pathway kinases, protein kinase C, mitogen-activated protein kinase, glycogen synthase kinase, casein kinase, integrin-linked kinase, sphingosine kinase, and kinases involved in the unfolded protein response.
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Affiliation(s)
- Hanley N Abramson
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA
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24
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Heusschen R, Muller J, Binsfeld M, Marty C, Plougonven E, Dubois S, Mahli N, Moermans K, Carmeliet G, Léonard A, Baron F, Beguin Y, Menu E, Cohen-Solal M, Caers J. SRC kinase inhibition with saracatinib limits the development of osteolytic bone disease in multiple myeloma. Oncotarget 2017; 7:30712-29. [PMID: 27095574 PMCID: PMC5058712 DOI: 10.18632/oncotarget.8750] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 03/31/2016] [Indexed: 12/17/2022] Open
Abstract
Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models. In vitro data showed an inhibitory effect of saracatinib on osteoclast differentiation, polarization and resorptive function. In osteoblasts, collagen deposition and matrix mineralization were affected by saracatinib. MM cell proliferation and tumor burden remained unaltered following saracatinib treatment and we could not detect any synergistic effects with drugs that are part of standard care in MM. We observed a marked reduction of bone loss after treatment of MM-bearing mice with saracatinib as reflected by a restoration of trabecular bone parameters to levels observed in naive control mice. Histomorphometric analyses support that this occurs through an inhibition of bone resorption. In conclusion, these data further establish SRC inhibition as a promising therapeutic approach for the treatment of MM-associated osteolytic bone disease.
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Affiliation(s)
- Roy Heusschen
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium
| | - Joséphine Muller
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium
| | - Marilène Binsfeld
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium
| | - Caroline Marty
- INSERM-UMR-1132, Hôpital Lariboisière and Université Paris Diderot, Paris, France
| | - Erwan Plougonven
- Department of Chemical Engineering, PEPs (Products, Environments, Processes), University of Liège, Liège, Belgium
| | - Sophie Dubois
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium
| | - Nadia Mahli
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium
| | - Karen Moermans
- Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Angélique Léonard
- Department of Chemical Engineering, PEPs (Products, Environments, Processes), University of Liège, Liège, Belgium
| | - Frédéric Baron
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.,Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium
| | - Yves Beguin
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.,Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium
| | - Eline Menu
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Martine Cohen-Solal
- INSERM-UMR-1132, Hôpital Lariboisière and Université Paris Diderot, Paris, France
| | - Jo Caers
- Laboratory of Hematology, GIGA-Research, University of Liège, Liège, Belgium.,Division of Hematology, Department of Medicine, University and CHU of Liège, Liège, Belgium
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25
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Bosseboeuf A, Allain-Maillet S, Mennesson N, Tallet A, Rossi C, Garderet L, Caillot D, Moreau P, Piver E, Girodon F, Perreault H, Brouard S, Nicot A, Bigot-Corbel E, Hermouet S, Harb J. Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins. Front Immunol 2017; 8:1347. [PMID: 29098000 PMCID: PMC5653692 DOI: 10.3389/fimmu.2017.01347] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 10/03/2017] [Indexed: 12/21/2022] Open
Abstract
Multiple myeloma (MM) and its pre-cancerous stage monoclonal gammopathy of undetermined significance (MGUS) allow to study immune responses and the chronology of inflammation in the context of blood malignancies. Both diseases are characterized by the production of a monoclonal immunoglobulin (mc Ig) which for subsets of MGUS and MM patients targets pathogens known to cause latent infection, a major cause of inflammation. Inflammation may influence the structure of both polyclonal (pc) Ig and mc Ig produced by malignant plasma cells via the sialylation of Ig Fc fragment. Here, we characterized the sialylation of purified mc and pc IgGs from 148 MGUS and MM patients, in comparison to pc IgGs from 46 healthy volunteers. The inflammatory state of patients was assessed by the quantification in serum of 40 inflammation-linked cytokines, using Luminex technology. While pc IgGs from MGUS and MM patients showed heterogeneity in sialylation level, mc IgGs from both MGUS and MM patients exhibited a very low level of sialylation. Furthermore, mc IgGs from MM patients were less sialylated than mc IgGs from MGUS patients (p < 0.01), and mc IgGs found to target an infectious pathogen showed a lower level of sialylation than mc IgGs of undetermined specificity (p = 0.048). Regarding inflammation, 14 cytokines were similarly elevated with a p value < 0.0001 in MGUS and in MM compared to healthy controls. MM differed from MGUS by higher levels of HGF, IL-11, RANTES and SDF-1-α (p < 0.05). MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (p < 0.05). In MGUS and in MM, the degree of sialylation of mc and pc IgGs and the levels of four cytokines important for the anti-microbial response were correlated, either positively (IFN-α2, IL-13) or negatively (IL-17, IL-33). Thus in MGUS as in MM, hyposialylation of mc IgGs is concomitant with increased levels of cytokines that play a major role in inflammation and anti-microbial response, which implies that infection, inflammation, and abnormal immune response contribute to the pathogenesis of MGUS and MM.
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Affiliation(s)
- Adrien Bosseboeuf
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France
| | - Sophie Allain-Maillet
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France
| | - Nicolas Mennesson
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France
| | - Anne Tallet
- Laboratoire de Biochimie, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Cédric Rossi
- Clinical Hematology, Centre Hospitalier Universitaire De Dijon, Dijon, France
| | - Laurent Garderet
- UMRS938, INSERM Institut National de la Santé et de la Recherche Médicale, Paris, France.,Département d'Hématologie et de Thérapie Cellulaire, Hôpital Saint Antoine, Paris, France.,UPMC Université Paris 6, Sorbonne Universités, Paris, France
| | - Denis Caillot
- Clinical Hematology, Centre Hospitalier Universitaire De Dijon, Dijon, France
| | - Philippe Moreau
- Hematology Department, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - Eric Piver
- Laboratoire de Biochimie, Centre Hospitalier Universitaire de Tours, Tours, France.,UMR966, INSERM Institut National de la Santé et de la Recherche Médicale, Tours, France
| | - François Girodon
- Laboratoire d'Hématologie, Centre Hospitalier Universitaire De Dijon, Dijon, France
| | - Hélène Perreault
- Department of Chemistry, University of Manitoba, Winnipeg, MB, Canada
| | - Sophie Brouard
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Institut National de la Santé et de la Recherche Médicale, Université de Nantes, Nantes, France
| | - Arnaud Nicot
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Institut National de la Santé et de la Recherche Médicale, Université de Nantes, Nantes, France
| | - Edith Bigot-Corbel
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France.,Laboratoire de Biochimie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.,Faculté de Pharmacie, Université de Nantes, Nantes, France
| | - Sylvie Hermouet
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France.,Faculté de Médecine, Université de Nantes, Nantes, France.,Laboratoire d'Hématologie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - Jean Harb
- CRCINA, INSERM, Institut de Recherche en Santé 2 (IRS-2), Université de Nantes, Nantes, France.,Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Institut National de la Santé et de la Recherche Médicale, Université de Nantes, Nantes, France.,Laboratoire de Biochimie, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France.,Faculté de Médecine, Université de Nantes, Nantes, France
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26
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Endothelial progenitor cells in multiple myeloma neovascularization: a brick to the wall. Angiogenesis 2017; 20:443-462. [PMID: 28840415 DOI: 10.1007/s10456-017-9571-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 07/31/2017] [Indexed: 12/12/2022]
Abstract
Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow that leads to events such as bone destruction, anaemia and renal failure. Despite the several therapeutic options available, there is still no effective cure, and the standard survival is up to 4 years. The evolution from the asymptomatic stage of monoclonal gammopathy of undetermined significance to MM and the progression of the disease itself are related to cellular and molecular alterations in the bone marrow microenvironment, including the development of the vasculature. Post-natal vasculogenesis is characterized by the recruitment to the tumour vasculature of bone marrow progenitors, known as endothelial progenitor cells (EPCs), which incorporate newly forming blood vessels and differentiate into endothelial cells. Several processes related to EPCs, such as recruitment, mobilization, adhesion and differentiation, are tightly controlled by cells and molecules in the bone marrow microenvironment. In this review, the bone marrow microenvironment and the mechanisms associated to the development of the neovasculature promoted by EPCs are discussed in detail in both a non-pathological scenario and in MM. The latest developments in therapy targeting the vasculature and EPCs in MM are also highlighted. The identification and characterization of the pathways relevant to the complex setting of MM are of utter importance to identify not only biomarkers for an early diagnosis and disease progression monitoring, but also to reveal intervention targets for more effective therapy directed to cancer cells and the endothelial mediators relevant to neovasculature development.
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27
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Logic programming reveals alteration of key transcription factors in multiple myeloma. Sci Rep 2017; 7:9257. [PMID: 28835615 PMCID: PMC5569101 DOI: 10.1038/s41598-017-09378-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 07/25/2017] [Indexed: 01/24/2023] Open
Abstract
Innovative approaches combining regulatory networks (RN) and genomic data are needed to extract biological information for a better understanding of diseases, such as cancer, by improving the identification of entities and thereby leading to potential new therapeutic avenues. In this study, we confronted an automatically generated RN with gene expression profiles (GEP) from a cohort of multiple myeloma (MM) patients and normal individuals using global reasoning on the RN causality to identify key-nodes. We modeled each patient by his or her GEP, the RN and the possible automatically detected repairs needed to establish a coherent flow of the information that explains the logic of the GEP. These repairs could represent cancer mutations leading to GEP variability. With this reasoning, unmeasured protein states can be inferred, and we can simulate the impact of a protein perturbation on the RN behavior to identify therapeutic targets. We showed that JUN/FOS and FOXM1 activities are altered in almost all MM patients and identified two survival markers for MM patients. Our results suggest that JUN/FOS-activation has a strong impact on the RN in view of the whole GEP, whereas FOXM1-activation could be an interesting way to perturb an MM subgroup identified by our method.
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28
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Abstract
Multiple myeloma (MM) mainly progresses in bone marrow (BM). Therefore, signals from the BM microenvironment are thought to play a critical role in maintaining plasma cell growth, migration, and survival. Reciprocal positive and negative interactions between plasma cells and microenvironmental cells, including endothelial cells (ECs) and fibroblasts may occur. The BM neovascularization is a constant hallmark of MM, and goes hand in hand with progression to leukemic phase. Microenvironmental factors induce MMECs and fibroblasts to become functionally different from monoclonal gammopathy of undetermined significance (MGUS) ECs (MGECs), i.e., to acquire an overangiogenic phenotype, and be similar to transformed cells. These alterations play an important role in MM progression and may represent new molecular markers for prognostic stratification of patients and prediction of response to antiangiogenic drugs, as well as new potential therapeutic targets.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School "Aldo Moro", Piazza G. Cesare, 11, 70124, Bari, Italy.
- National Cancer Institute, Giovanni Paolo II, Bari, Italy.
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology (DIMO), Section of Internal Medicine "G. Baccelli", University of Bari Medical School "Aldo Moro", Piazza Giulio Cesare, 11, 70124, Bari, Italy.
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29
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Abdollahi P, Vandsemb EN, Hjort MA, Misund K, Holien T, Sponaas AM, Rø TB, Slørdahl TS, Børset M. Src Family Kinases Are Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3. Mol Cancer Res 2016; 15:69-77. [DOI: 10.1158/1541-7786.mcr-16-0212] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/19/2016] [Accepted: 09/22/2016] [Indexed: 11/16/2022]
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30
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de la Puente P, Azab F, Muz B, Luderer M, Arbiser J, Azab AK. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma. Leuk Lymphoma 2015; 57:1677-86. [PMID: 26421357 DOI: 10.3109/10428194.2015.1099645] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.
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Affiliation(s)
- Pilar de la Puente
- a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA
| | - Feda Azab
- a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA
| | - Barbara Muz
- a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA
| | - Micah Luderer
- a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA
| | - Jack Arbiser
- b Department of Dermatology , Emory University School of Medicine , Atlanta , GA , USA.,c Atlanta Veterans Administration Health Center , Atlanta , GA , USA
| | - Abdel Kareem Azab
- a Department of Radiation Oncology , Cancer Biology Division, Washington University in Saint Louis School of Medicine , St. Louis , MO , USA
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31
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Păunescu E, Clavel CM, Nowak-Sliwinska P, Griffioen AW, Dyson PJ. Improved angiostatic activity of dasatinib by modulation with hydrophobic chains. ACS Med Chem Lett 2015; 6:313-7. [PMID: 25815152 DOI: 10.1021/ml500496u] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 01/30/2015] [Indexed: 12/21/2022] Open
Abstract
Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-β and SFKs in both tumor cells and tumor-associated endothelial cells, dasatinib inhibits tumor growth and angiogenesis. Herein, dasatinib derivatives modified with hydrophobic chains were prepared and evaluated for their in vitro antiproliferative selectivity and their in vivo antiangiogenic activity. For one of the derivatives, modified with a long perfluorinated chain, a significant enhancement in antiangiogenic activity was observed. Combined, these results suggest a possible generic route to modulate the angiostatic activity of drugs.
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Affiliation(s)
- Emilia Păunescu
- Institut
des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Catherine M. Clavel
- Institut
des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Patrycja Nowak-Sliwinska
- Institut
des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Arjan W. Griffioen
- Angiogenesis
Laboratory, Department of Medical Oncology, VUMC Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Paul J. Dyson
- Institut
des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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32
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Abstract
In patients with multiple myeloma (MM), the bone marrow (BM) contains hematopoietic stem cells (HSCs) and non-hematopoietic cells. HSCs are able to give rise to all types of mature blood cells, while the non hematopoietic component includes mesenchymal stem cells (MSCs), fibroblasts, osteoblasts, osteoclasts, chondroclasts, endothelial cells, endothelial progenitor cells (EPCs), B and T lymphocytes, NK cells, erythrocytes, megakaryocytes, platelets, macrophages and mast cells. All of these cells form specialized "niches" in the BM microenvironment which are close to the vasculature ("vascular niche") or to the endosteum ("osteoblast niche"). The "vascular niche" is rich in blood vessels where endothelial cells and mural cells (pericytes and smooth muscle cells) create a microenvironment that affects the behavior of several stem and progenitor cells. The vessel wall serves as an independent niche for the recruitment of endothelial progenitor cells, MSCs and HSCs. The activation by angiogenic factors and inflammatory cytokines switch the "vascular niche" to promote MM tumor growth and spread. This review will focus on the mechanisms involved in the generation of signals released by endothelial cells in the "vascular niche" that promote tumor growth and spread in MM.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy.
| | - Michele Moschetta
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
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33
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Di Noto G, Chiarini M, Paolini L, Mazzoldi EL, Giustini V, Radeghieri A, Caimi L, Ricotta D. Immunoglobulin Free Light Chains and GAGs Mediate Multiple Myeloma Extracellular Vesicles Uptake and Secondary NfκB Nuclear Translocation. Front Immunol 2014; 5:517. [PMID: 25386176 PMCID: PMC4209816 DOI: 10.3389/fimmu.2014.00517] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 10/04/2014] [Indexed: 01/08/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy caused by a microenviromentally aided persistence of plasma cells in the bone marrow. Monoclonal plasma cells often secrete high amounts of immunoglobulin free light chains (FLCs) that could induce tissue damage. Recently, we showed that FLCs are internalized in endothelial and myocardial cell lines and secreted in extracellular vesicles (EVs). MM serum derived EVs presented phenotypic differences if compared with monoclonal gammopathy of undetermined significance (MGUS) serum derived EVs suggesting their involvement in MM pathogenesis or progression. To investigate the effect of circulating EVs on endothelial and myocardial cells, we purified MM and MGUS serum derived EVs with differential ultracentrifugation protocols and tested their biological activity. We found that MM and MGUS EVs induced different proliferation and internalization rates in endothelial and myocardial cells, thus we tried to find specific targets in MM EVs docking and processing. Pre-treatment of EVs with anti-FLCs antibodies or heparin blocked the MM EVs uptake, highlighting that FLCs and glycosaminoglycans are involved. Indeed, only MM EVs exposure induced a strong nuclear factor kappa B nuclear translocation that was completely abolished after anti-FLCs antibodies and heparin pre-treatment. The protein tyrosine kinase c-src is present on MM circulating EVs and redistributes to the cell plasma membrane after MM EVs exposure. The anti-FLCs antibodies and heparin pre-treatments were able to block the intracellular re-distribution of the c-src kinase and the subsequent c-src kinase containing EVs production. Our results open new insights in EVs cellular biology and in MM therapeutic and diagnostic approaches.
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Affiliation(s)
- Giuseppe Di Noto
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
| | - Marco Chiarini
- CREA, Diagnostic Department, Azienda Ospedaliera Spedali Civili di Brescia , Brescia , Italy
| | - Lucia Paolini
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
| | - Elena Laura Mazzoldi
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
| | - Viviana Giustini
- CREA, Diagnostic Department, Azienda Ospedaliera Spedali Civili di Brescia , Brescia , Italy
| | - Annalisa Radeghieri
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
| | - Luigi Caimi
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
| | - Doris Ricotta
- Department of Molecular and Translational Medicine, Faculty of Medicine, University of Brescia , Brescia , Italy
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34
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Abstract
INTRODUCTION There is certain degree of frustration and discontent in the area of microarray gene expression data analysis of cancer datasets. It arises from the mathematical problem called 'curse of dimensionality,' which is due to the small number of samples available in training sets, used for calculating transcriptional signatures from the large number of differentially expressed (DE) genes, measured by microarrays. The new generation of causal reasoning algorithms can provide solutions to the curse of dimensionality by transforming microarray data into activity of a small number of cancer hallmark pathways. This new approach can make feature space dimensionality optimal for mathematical signature calculations. AREAS COVERED The author reviews the reasons behind the current frustration with transcriptional signatures derived from DE genes in cancer. He also provides an overview of the novel methods for signature calculations based on differentially variable genes and expression regulators. Furthermore, the authors provide perspectives on causal reasoning algorithms that use prior knowledge about regulatory events described in scientific literature to identify expression regulators responsible for the differential expression observed in cancer samples. EXPERT OPINION The author advocates causal reasoning methods to calculate cancer pathway activity signatures. The current challenge for these algorithms is in ensuring quality of the knowledgebase. Indeed, the development of cancer hallmark pathway collections, together with statistical algorithms to transform activity of expression regulators into pathway activity, are necessary for causal reasoning to be used in cancer research.
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Affiliation(s)
- Anton Yuryev
- Elsevier, Inc. , 5635 Fishers Lane, Rockville, MD 20852 USA
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35
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Korashy HM, Rahman AFMM, Kassem MG. Dasatinib. PROFILES OF DRUG SUBSTANCES, EXCIPIENTS, AND RELATED METHODOLOGY 2014; 39:205-37. [PMID: 24794907 DOI: 10.1016/b978-0-12-800173-8.00004-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Dasatinib (Sprycel®), a second-generation TKI, has been shown to be effective as an anticancer drug in the treatment of patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib. Several methods of gefitinib synthesis are included in this review. UV spectroscopy of dasatinib showed a λmax of approximately 320-330nm, and IR spectroscopy principal peaks were observed at 3418 (NH), 3200 (OH), 1620 (CO), 1582 (CC and CN), 1513 (CHCH) cm(-1). Characteristic NH peaks were observed in nuclear magnetic resonance (NMR) spectroscopy at 11.47 and 9.88ppm. The molecular mass was observed at m/z=487.3((35)Cl) and 488.9((37)Cl) (molecular weight=487.15) and the fragmentation pattern was studied using ion trap mass spectrometry. In addition, different analytical methods for determination of dasatinib are also described in this review. Pharmacokinetically, dasatinib is rapidly absorbed after oral administration where the solubility is dependent on pH. Dasatinib extensively binds to human plasma proteins by approximately 96%. In leukemic patient, the calculated apparent volume of distribution for dasatinib was 2502L and the estimated elimination half-life was approximately 3-5h. Dasatinib is metabolized in humans markedly by CYP3A4 to active metabolites and by phase II drug-metabolizing enzymes, such as UDP glucuronosyltransferase. Dasatinib is mainly eliminated via the feces (85%), of which relatively small amount of dasatinib is excreted unchanged as intact drug (19%). Most of the adverse effects associated with dasatinib therapy are mild to moderate in severity and are usually reversible and manageable with appropriate intervention, such as cardiac failure, hypertension, and coronary artery disease.
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Affiliation(s)
- Hesham M Korashy
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - A F M Motiur Rahman
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Gabr Kassem
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC, San Miguel JF, Garayoa M. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics. World J Stem Cells 2014; 6:322-343. [PMID: 25126382 PMCID: PMC4131274 DOI: 10.4252/wjsc.v6.i3.322] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/24/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.
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Yori JL, Lozada KL, Seachrist DD, Mosley JD, Abdul-Karim FW, Booth CN, Flask CA, Keri RA. Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. Cancer Res 2014; 74:4762-71. [PMID: 25023728 DOI: 10.1158/0008-5472.can-13-3627] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Resistance to receptor tyrosine kinase (RTK) blockade in breast cancer is often mediated by activation of bypass pathways that sustain growth. Src and mammalian target of rapamycin (mTOR) are two intrinsic targets that are downstream of most RTKs. To date, limited clinical efficacy has been observed with either Src or mTOR inhibitors when used as single agents. Resistance to mTOR inhibitors is associated with loss of negative feedback regulation, resulting in phosphorylation and activation of AKT. Herein, we describe a novel role for Src in contributing to rapalog-induced AKT activation. We found that dual activation of Src and the mTOR pathway occurs in nearly half of all breast cancers, suggesting potential cross-talk. As expected, rapamycin inhibition of mTOR results in feedback activation of AKT in breast cancer cell lines. Addition of the Src/c-Abl inhibitor, dasatinib, completely blocks this feedback activation, confirming convergence between Src and the mTOR pathway. Analysis in vivo revealed that dual Src and mTOR inhibition is highly effective in two mouse models of breast cancer. In a luminal disease model, combined dasatinib and rapamycin is more effective at inducing regression than either single agent. Furthermore, the combination of dasatinib and rapamycin delays tumor recurrence following the cessation of treatment. In a model of human EGFR-2-positive (HER2(+)) disease, dasatinib alone is ineffective, but potentiates the efficacy of rapamycin. These data suggest that combining mTOR and Src inhibitors may provide a new approach for treating multiple breast cancer subtypes that may circumvent resistance to targeted RTK therapies.
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Affiliation(s)
- Jennifer L Yori
- Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Kristen L Lozada
- Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Darcie D Seachrist
- Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Jonathan D Mosley
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Fadi W Abdul-Karim
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Christine N Booth
- Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Chris A Flask
- Department of Radiology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Biomedical Engineering, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Pediatrics, Case Western Reserve University, School of Medicine, Cleveland, Ohio
| | - Ruth A Keri
- Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio. Department of Genetics and Division of General Medical Sciences-Oncology, Case Western Reserve University, School of Medicine, Cleveland, Ohio.
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Withacnistin inhibits recruitment of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumours. Br J Cancer 2014; 111:894-902. [PMID: 24983364 PMCID: PMC4150266 DOI: 10.1038/bjc.2014.349] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/14/2014] [Accepted: 05/14/2014] [Indexed: 01/05/2023] Open
Abstract
Background: The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anticancer agents. Methods: Co-immunoprecipitation, western blotting, microscopy, DNA binding, invasion, and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin (Wit) inhibits STAT 3/5 tyrosine phosphoryaltion and activation. Results: Wit blocks EGF- and IL-6-stimulated binding of STAT3 and STAT5 to EGFR and gp130. Wit inhibits EGF-, PDGF-, IL-6-, IFNβ-, and GM-CSF-stimulation of tyrosine phosphorylation of STAT3 and STAT5 but not of EGFR or PDGFR. The inhibition of P-STAT3 and P-STAT5 occurred rapidly, within minutes of Wit treatment and growth factor stimulation. Wit also inhibits STAT3 nuclear translocation, DNA binding, promoter transcriptional activation, and it suppresses the expression levels of STAT3 target genes such as Bcl-xL and Mcl-1. Finally, Wit induces apoptosis, inhibits anchorage-dependent and -independent growth and invasion, and causes breast tumour regression in an ErbB2-driven transgenic mouse model. Conclusions: These data warrant further development of Wit as a novel anticancer drug for targeting tumours that harbour hyperactivated STAT3 and STAT5.
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Keane NA, Glavey SV, Krawczyk J, O'Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets 2014; 18:897-915. [PMID: 24905897 DOI: 10.1517/14728222.2014.924507] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Multiple myeloma remains an incurable malignancy with poor survival. Novel therapeutic approaches capable of improving outcomes in patients with multiple myeloma are urgently required. AKT is a central node in the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin signaling pathway with high expression in advanced and resistant multiple myeloma. AKT contributes to multiple oncogenic functions in multiple myeloma which may be exploited therapeutically. Promising preclinical data has lent support for pursuing further development of AKT inhibitors in multiple myeloma. Lead drugs are now entering the clinic. AREAS COVERED The rationale for AKT inhibition in multiple myeloma, pharmacological subtypes of AKT inhibitors in development, available results of clinical studies of AKT inhibitors and suitable drug partners for further development in combination with AKT inhibition in multiple myeloma are discussed. EXPERT OPINION AKT inhibitors are a welcome addition to the armamentarium against multiple myeloma and promising clinical activity is being reported from ongoing trials in combination with established and/or novel treatment approaches. AKT inhibitors may be set to improve patient outcomes when used in combination with synergistic drug partners.
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Affiliation(s)
- Niamh A Keane
- Galway University Hospital, Department of Haematology , Newcastle Road, Galway , Ireland
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Dasatinib targets B-lineage cells but does not provide an effective therapy for myeloproliferative disease in c-Cbl RING finger mutant mice. PLoS One 2014; 9:e94717. [PMID: 24718698 PMCID: PMC3981816 DOI: 10.1371/journal.pone.0094717] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 03/18/2014] [Indexed: 11/30/2022] Open
Abstract
This study aimed to determine whether the multi-kinase inhibitor dasatinib would provide an effective therapy for myeloproliferative diseases (MPDs) involving c-Cbl mutations. These mutations, which occur in the RING finger and linker domains, abolish the ability of c-Cbl to function as an E3 ubiquitin ligase and downregulate activated protein tyrosine kinases. Here we analyzed the effects of dasatinib in a c-Cbl RING finger mutant mouse that develops an MPD with a phenotype similar to the human MPDs. The mice are characterized by enhanced tyrosine kinase signaling resulting in an expansion of hematopoietic stem cells, multipotent progenitors and cells within the myeloid lineage. Since c-Cbl is a negative regulator of c-Kit and Src signaling we reasoned that dasatinib, which targets these kinases, would be an effective therapy. Furthermore, two recent studies showed dasatinib to be effective in inhibiting the in vitro growth of cells from leukemia patients with c-Cbl RING finger and linker domain mutations. Surprisingly we found that dasatinib did not provide an effective therapy for c-Cbl RING finger mutant mice since it did not suppress any of the hematopoietic lineages that promote MPD development. Thus we conclude that dasatinib may not be an appropriate therapy for leukemia patients with c-Cbl mutations. We did however find that dasatinib caused a marked reduction of pre-B cells and immature B cells which correlated with a loss of Src activity. This study is therefore the first to provide a detailed characterization of in vivo effects of dasatinib in a hematopoietic disorder that is driven by protein tyrosine kinases other than BCR-ABL.
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Lowe DB, Bose A, Taylor JL, Tawbi H, Lin Y, Kirkwood JM, Storkus WJ. Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology 2014; 3:e27589. [PMID: 24734217 PMCID: PMC3984268 DOI: 10.4161/onci.27589] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 12/18/2013] [Accepted: 12/18/2013] [Indexed: 12/16/2022] Open
Abstract
Dasatinib (DAS) is a potent inhibitor of the BCR-ABL, SRC, c-KIT, PDGFR, and ephrin tyrosine kinases that has demonstrated only modest clinical efficacy in melanoma patients. Given reports suggesting that DAS enhances T cell infiltration into the tumor microenvironment, we analyzed whether therapy employing the combination of DAS plus dendritic cell (DC) vaccination would promote superior immunotherapeutic benefit against melanoma. Using a M05 (B16.OVA) melanoma mouse model, we observed that a 7-day course of orally-administered DAS (0.1 mg/day) combined with a DC-based vaccine (VAC) against the OVA257–264 peptide epitope more potently inhibited tumor growth and extended overall survival as compared with treatment with either single modality. The superior efficacy of the combinatorial treatment regimen included a reduction in hypoxic-signaling associated with reduced levels of immunosuppressive CD11b+Gr1+ myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ regulatory T (Treg) populations in the melanoma microenvironment. Furthermore, DAS + VAC combined therapy upregulated expression of Type-1 T cell recruiting CXCR3 ligand chemokines in the tumor stroma correlating with activation and recruitment of Type-1, vaccine-induced CXCR3+CD8+ tumor-infiltrating lymphocytes (TILs) and CD11c+ DC into the tumor microenvironment. The culmination of this bimodal approach was a profound “spreading” in the repertoire of tumor-associated antigens recognized by CD8+ TILs, in support of the therapeutic superiority of combined DAS + VAC immunotherapy in the melanoma setting.
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Affiliation(s)
- Devin B Lowe
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Anamika Bose
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Jennifer L Taylor
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
| | - Hussein Tawbi
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - Yan Lin
- Department of Biostatistics; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - John M Kirkwood
- Department of Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
| | - Walter J Storkus
- Department of Dermatology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute; Pittsburgh, PA USA
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Byrne M, Katz J, Moreb J. Multiple Myeloma and Evolution of Novel Biomarkers and Therapies. Cancer Biomark 2014. [DOI: 10.1201/b16389-39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells. Leuk Res 2014; 38:121-30. [DOI: 10.1016/j.leukres.2013.10.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 10/17/2013] [Accepted: 10/19/2013] [Indexed: 11/23/2022]
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High-performance liquid chromatographic method for the determination of dasatinib in rabbit plasma using fluorescence detection and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 939:73-9. [DOI: 10.1016/j.jchromb.2013.09.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Revised: 09/05/2013] [Accepted: 09/06/2013] [Indexed: 11/23/2022]
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Abstract
The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free survival (PFS) and overall survival (OS) in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next 5 years.
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Affiliation(s)
- Robert Z Orlowski
- Department of Lymphoma/Myeloma, and Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
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46
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Jungkunz-Stier I, Zekl M, Stühmer T, Einsele H, Seggewiss-Bernhardt R. Modulation of natural killer cell effector functions through lenalidomide/dasatinib and their combined effects against multiple myeloma cells. Leuk Lymphoma 2013; 55:168-76. [PMID: 23573828 DOI: 10.3109/10428194.2013.794270] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The multikinase inhibitor dasatinib blocks the constitutive activation of oncogenic Src kinases in multiple myeloma (MM) cells and potentially enhances natural killer (NK) cell activity. Therefore, we tested combination effects of dasatinib and lenalidomide regarding MM cell viability and NK cell effector functions. The drug combination mostly had little influence on the viability of MM cell lines, and produced mixed results on primary MM cells. Prolonged lenalidomide treatment enhanced NK cell effector functions, and dasatinib addition at late stages of NK cell expansion increased levels of CD107a/b and interferon-γ (IFNγ), but not of tumor necrosis factor-α (TNFα). Additive effects were observed for the enhancement of cytokine production and degranulation, but only lenalidomide increased NK cell cytotoxicity against MM cells. This effect correlated with increased TNF-related apoptosis-inducing ligand (TRAIL) expression and was attenuated by dasatinib, or suppressors of TRAIL or TNFα. Our data thus indicate a functional role for the TRAIL/TRAIL-R system in lenalidomide-mediated NK-cell activity against MM cells, but also show that dasatinib is unsuitable to support or boost this effect.
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Henderson YC, Toro-Serra R, Chen Y, Ryu J, Frederick MJ, Zhou G, Gallick GE, Lai SY, Clayman GL. Src inhibitors in suppression of papillary thyroid carcinoma growth. Head Neck 2013; 36:375-84. [PMID: 23729178 DOI: 10.1002/hed.23316] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2013] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Papillary thyroid carcinoma is the most common thyroid malignancy. Most papillary thyroid carcinomas contain BRAF mutations or RET/PTC rearrangements, thus providing targets for biologic therapy. Our previous studies had suggested papillary thyroid carcinomas (PTCs) with a BRAF mutation and the RET/PTC1 rearrangement have different sensitivities to MEK1/2 inhibitors, suggesting different signaling transduction pathways were involved. METHODS Src signaling transduction pathway in PTC cells was examined using Src inhibitors (PP2, SU6656, or dasatinib) and si-Src RNA in vitro by Western blot analysis and proliferation analysis. An orthotopic xenograft mouse model was used for the in vivo studies using dasatinib. RESULTS In PTC cells, Src inhibitors suppressed p-Src and p-FAK and inhibited cell growth. In addition, significant suppression and extension of the p-ERK1/2 dephosphorylation were detected in RET/PTC1-rearranged cells in combination with an MEK inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib, significantly decreased tumor volume in mice inoculated with PTC cells carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src inhibitors effectively suppressed p-Src expression and dasatinib significantly decreased tumor volume with twice daily treatment. CONCLUSION Src inhibitors effectively inhibited the Src signaling transduction pathway in PTC cells in vitro and dasatinib suppressed tumor growth in vivo. These results suggested that Src signaling transduction pathway plays an important role in regulating growth in PTC cells. Combination of Src and MEK1/2 inhibitors extended the dephosphorylation of extracellular signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1 rearrangement suggesting that combination therapy with complementary inhibitors of other signaling transduction pathways may be needed to effectively suppress growth and induce apoptosis in these cells.
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Affiliation(s)
- Ying C Henderson
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Otjacques E, Binsfeld M, Rocks N, Blacher S, Vanderkerken K, Noel A, Beguin Y, Cataldo D, Caers J. Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. PLoS One 2013; 8:e62818. [PMID: 23667526 PMCID: PMC3646989 DOI: 10.1371/journal.pone.0062818] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 03/26/2013] [Indexed: 01/03/2023] Open
Abstract
Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.
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Affiliation(s)
- Eléonore Otjacques
- Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
- Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Marilène Binsfeld
- Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Natacha Rocks
- Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Silvia Blacher
- Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Karin Vanderkerken
- Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
| | - Agnès Noel
- Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Yves Beguin
- Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Didier Cataldo
- Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
| | - Jo Caers
- Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium
- * E-mail:
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Tassone P, Neri P, Burger R, Di Martino MT, Leone E, Amodio N, Caraglia M, Tagliaferri P. Mouse models as a translational platform for the development of new therapeutic agents in multiple myeloma. Curr Cancer Drug Targets 2013; 12:814-22. [PMID: 22671927 PMCID: PMC3587184 DOI: 10.2174/156800912802429292] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 11/25/2011] [Accepted: 12/08/2011] [Indexed: 12/22/2022]
Abstract
Mouse models of multiple myeloma (MM) are basic tools for translational research and play a fundamental role in the development of new therapeutics against plasma cell malignancies. All available models, including transplantable murine tumors in syngenic mice, xenografts of established human cell lines in immunocompromised mice and transgenic models that mirror specific steps of MM pathogenesis, have demonstrated some weaknesses in predicting clinical results, particularly for new drugs targeting the human bone marrow microenvironment (huBMM). The recent interest to models recapitulating the in vivo growth of primary MM cells in a human (SCID-hu) or humanized (SCID-synth-hu) host recipient has provided powerful platforms for the investigation of new compounds targeting MM and/or its huBMM. Here, we review and discuss strengths and weaknesses of the key in vivo models that are currently utilized in the MM preclinical investigation.
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Affiliation(s)
- P Tassone
- Medical Oncology, Magna Græcia University, Viale Europa, Campus Salvatore Venuta, 88100 Catanzaro, Italy.
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Kharaziha P, De Raeve H, Fristedt C, Li Q, Gruber A, Johnsson P, Kokaraki G, Panzar M, Laane E, Osterborg A, Zhivotovsky B, Jernberg-Wiklund H, Grandér D, Celsing F, Björkholm M, Vanderkerken K, Panaretakis T. Sorafenib has potent antitumor activity against multiple myeloma in vitro, ex vivo, and in vivo in the 5T33MM mouse model. Cancer Res 2012; 72:5348-62. [PMID: 22952216 DOI: 10.1158/0008-5472.can-12-0658] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of clonal plasma blasts/plasma cells within the bone marrow that relies on multiple signaling cascades, including tyrosine kinase activated pathways, to proliferate and evade cell death. Despite emerging new treatment strategies, multiple myeloma remains at present incurable. Thus, novel approaches targeting several signaling cascades by using the multi-tyrosine kinase inhibitor (TKI), sorafenib, seem a promising treatment approach for multiple myeloma. Here, we show that sorafenib induces cell death in multiple myeloma cell lines and in CD138(+)-enriched primary multiple myeloma patient samples in a caspase-dependent and -independent manner. Furthermore, sorafenib has a strong antitumoral and -angiogenic activity in the 5T33MM mouse model leading to increased overall survival. Multiple myeloma cells undergo autophagy in response to sorafenib, and inhibition of this cytoprotective pathway potentiated the efficacy of this TKI. Mcl-1, a survival factor in multiple myeloma, is downregulated at the protein level by sorafenib allowing for the execution of cell death, as ectopic overexpression of this protein protects multiple myeloma cells. Concomitant targeting of Mcl-1 by sorafenib and of Bcl-2/Bcl-xL by the antagonist ABT737 improves the efficacy of sorafenib in multiple myeloma cell lines and CD138(+)-enriched primary cells in the presence of bone marrow stromal cells. Altogether, our data support the use of sorafenib as a novel therapeutic modality against human multiple myeloma, and its efficacy may be potentiated in combination with ABT737.
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Affiliation(s)
- Pedram Kharaziha
- Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska University Hospital Solna, Stockholm, Sweden
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