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Article ; Online: BML-260 promotes the growth of cord blood and mobilized peripheral blood hematopoietic stem and progenitor cells with improved reconstitution ability.

Albayrak, Esra / Akgol, Sezer / Turan, Raife Dilek / Uslu, Merve / Kocabas, Fatih

2022

Abstract: Hematopoietic stem cells (HSCs), which are multipotent and have the ability to self-renew, are frequently used in the treatment of hematological diseases and cancer. Small molecules that target HSC quiescence regulators could be used for ex vivo ... ...

Abstract	Hematopoietic stem cells (HSCs), which are multipotent and have the ability to self-renew, are frequently used in the treatment of hematological diseases and cancer. Small molecules that target HSC quiescence regulators could be used for ex vivo expansion of both mobilized peripheral blood (mPB) and umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPC). We identified and investigated 35 small molecules that target HSC quiescence factors. We looked at how they affected HSC activity, such as expansion, quiescence, multilineage capacity, cycling ability, metabolism, cytotoxicity, and genotoxicity. A transplantation study was carried out on immunocompromised mice to assess the expanded cells' repopulation and engraftment abilities. 4-[(5Z)-5-benzylidene-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]benzoic acid (BML)-260 and tosyl-l-arginine methyl ester (TAME) significantly increased both mPB and UCB-HSPC content and activated HSC re-entry into the cell cycle. The improved multilineage capacity was confirmed by the colony forming unit (CFU) assay. Furthermore, gene expression analysis revealed that BML-260 and TAME molecules aided HSC expansion by modulating cell cycle kinetics, such as p27, SKP2, and CDH1. In addition to these in vitro findings, we discovered that BML-260-expanded HSCs had a high hematopoietic reconstitution capacity with increased immune cell content after xenotransplantation into immunocompromised mice. In addition to the BML-260 molecule, a comparison study of serum-containing and serum-free chemically defined media, including various supplements, was performed. These in vitro and xenotransplantation results show that BML-260 molecules can be used for human HSC expansion and regulation of function. Furthermore, the medium composition discovered may be a novel platform for human HSPC expansion that could be used in clinical trials.
Language	English
Publishing date	2022-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.30324
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Zs.A 1114: Show issues

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Article ; Online: Lentiviral Micro-dystrophin Gene Treatment into Late-stage mdx Mice for Duchenne Muscular Dystrophy Disease.

Eren, Selen Abanuz / Tastan, Cihan / Karadeniz, Kevser Buse / Turan, Raife Dilek / Cakirsoy, Didem / Kancagi, Derya Dilek / Yilmaz, Sevdican Ustun / Oztatlici, Mustafa / Oztatlici, Hulya / Ozer, Samed / Tumentemur, Gamze / Baykal, Ahmet Tarık / Ovali, Ercument

Current gene therapy

2023 Volume 23, Issue 4, Page(s) 304–315

Abstract: Aim: Duchenne Muscular Dystrophy (DMD) results in a deficiency of dystrophin expression in patient muscle fibers, leading to progressive muscle degeneration. Treatment of DMD has undertaken current transformation with the advancement of novel gene ... ...

Abstract	Aim: Duchenne Muscular Dystrophy (DMD) results in a deficiency of dystrophin expression in patient muscle fibers, leading to progressive muscle degeneration. Treatment of DMD has undertaken current transformation with the advancement of novel gene therapy and molecular biology techniques, which are secure, well-tolerated, and effective therapeutic approaches. Introduction: DMD gene therapies have mainly focused on young DMD patients as in vivo animal model trials have been performed in 0-1-month DMD mice. However, it has not yet been answered how micro-dystrophin encoding lentiviral treatment affects Dystrophin expression and DMD symptoms in 10-month mdx mice. Methods: We planned to integrate the micro-Dystrophin gene sequence into the muscle cells by viral transfer, using micro-Dystrophin-encoding lentivirus to reduce the dystrophic pathology in late-stage dmd mice. The histopathological and physiological-functional regeneration activities of the lentiviralmicro- Dystrophin gene therapy methods were compared, along with changes in temporal Dystrophin expression and their functionality, toxicity, and gene expression level. Results: Here, we showed that the micro-dystrophin transgene transfers intramuscularly and intraperitoneally in late-stage dmd-mdx-4cv mice restored dystrophin expression in the skeletal and cardiac muscle ( Conclusion: Consequently, this study suggests that patients in the late stages of muscular dystrophy can benefit from lentiviral micro-dystrophin gene therapies to present an improvement in dystrophic muscle pathology.
MeSH term(s)	Mice ; Animals ; Dystrophin/genetics ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/therapy ; Mice, Inbred mdx ; Genetic Therapy/methods ; Disease Models, Animal ; Muscle, Skeletal
Chemical Substances	Dystrophin
Language	English
Publishing date	2023-04-11
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146187-9
ISSN	1875-5631 ; 1566-5232
ISSN (online)	1875-5631
ISSN	1566-5232
DOI	10.2174/1566523223666230407091317
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Zs.A 5883: Show issues

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Article ; Online: Enhancing CAR-T cells: unleashing lasting impact potential with phytohemagglutinin activation in in vivo leukemia model.

Sert, Berranur / Gulden, Gamze / Teymur, Tarik / Ay, Yasin / Turan, Raife Dilek / Unaldi, Onur Mert / Guzenge, Elanur / Erdil, Hamza Emir / Isik, Sevim / Oz, Pinar / Bozkurt, Ilknur / Ozer, Samed / Yurdakul, Tahire / Kamali, Osman / Ovali, Ercument / Tarhan, Nevzat / Tastan, Cihan

Cancer gene therapy

2023 Volume 31, Issue 3, Page(s) 387–396

Abstract: Chimeric antigen receptor T (CAR-T) cell therapy holds great promise as an innovative immunotherapeutic approach for cancer treatment. To optimize the production and application of CAR-T cells, we evaluated the in vivo stability and efficacy capacities ... ...

Abstract	Chimeric antigen receptor T (CAR-T) cell therapy holds great promise as an innovative immunotherapeutic approach for cancer treatment. To optimize the production and application of CAR-T cells, we evaluated the in vivo stability and efficacy capacities of CAR-T cells developed under different conditions. In this study, CAR-T cells were activated using Phytohemagglutinin (PHA) or anti-CD3&anti-CD28 and were compared in an in vivo CD19+B-cell cancer model in mouse groups. Our results demonstrated that CAR-T cells activated with PHA exhibited higher stability and anti-cancer efficacy compared to those activated with anti-CD3&anti-CD28. Specifically, CAR19BB-T cells activated with PHA exhibited continuous proliferation and long-term persistence without compromising their anti-cancer efficacy. Kaplan-Meier survival analysis revealed prolonged overall survival in the CAR-T cell-treated groups compared to the only tumor group. Furthermore, specific LTR-targeted RT-PCR analysis confirmed the presence of CAR-T cells in the treated groups, with significantly higher levels observed in the CAR19BB-T (PHA) group compared to other groups. Histopathological analysis of spleen, kidney, and liver tissue sections indicated reduced inflammation and improved tissue integrity in the CAR-T cell-treated groups. Our findings highlight the potential benefits of using PHA as a co-stimulatory method for CAR-T cell production, offering a promising strategy to enhance their stability and persistence. These results provide valuable insights for the development of more effective and enduring immunotherapeutic approaches for cancer treatment. CAR-T cells activated with PHA may offer a compelling therapeutic option for advancing cancer immunotherapy in clinical applications.
MeSH term(s)	Mice ; Animals ; Phytohemagglutinins/pharmacology ; T-Lymphocytes ; Leukemia/therapy ; Immunotherapy, Adoptive/methods ; Neoplasms ; CD28 Antigens ; Antigens, CD19 ; Receptors, Antigen, T-Cell
Chemical Substances	Phytohemagglutinins ; CD28 Antigens ; Antigens, CD19 ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-12-14
Publishing country	England
Document type	Journal Article
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-023-00709-9
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Zs.A 4125: Show issues

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Article ; Online: Emerging Roles of Meis1 in Cardiac Regeneration, Stem Cells and Cancer.

Aksoz, Merve / Turan, Raife Dilek / Albayrak, Esra / Kocabas, Fatih

Current drug targets

2017 Volume 19, Issue 2, Page(s) 181–190

Abstract: Background: Meis1 is a member of three-amino-acid loop extension (TALE) homeodomain transcription factors. Studies in the last decade have shown that Meis1 has crucial roles in cardiac regeneration, stem cell function, and tumorigenesis.: Objective: ... ...

Abstract	Background: Meis1 is a member of three-amino-acid loop extension (TALE) homeodomain transcription factors. Studies in the last decade have shown that Meis1 has crucial roles in cardiac regeneration, stem cell function, and tumorigenesis. Objective: We have recently demonstrated that knocking out of Meis1 in adult cardiomyocytes resulted in the induction of cardiomyocyte proliferation. This suggests that targeting of Meis1 might be utilized in the manipulation of cardiomyocyte cell cycle post cardiac injuries. In addition, hematopoietic stem cell (HSC) specific deletion of Meis1 leads to in vivo expansion of HSCs pool. Thus, targeting Meis1 may lead to not only cell cycle entry but also ex vivo and in vivo expansion of HSCs. On the other hand, Meis1 transcriptionally regulates the expression of hypoxic tumor markers, namely Hif-1α and Hif-2α. Hif-1α and Hif-2α are involved in the induction of cytoplasmic glycolysis and scavenging of reactive oxygen species (ROS), respectively. Conclusion: Studies highlight emerging roles of Meis1 towards development of new therapeutic approaches in the treatment of myocardial injuries, bone failure, and cancer.
MeSH term(s)	Animals ; Apoptosis ; Biomarkers, Tumor/metabolism ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Cycle ; Cell Proliferation ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; Myeloid Ecotropic Viral Integration Site 1 Protein/genetics ; Myeloid Ecotropic Viral Integration Site 1 Protein/metabolism ; Myeloid Ecotropic Viral Integration Site 1 Protein/physiology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Regeneration
Chemical Substances	Biomarkers, Tumor ; Myeloid Ecotropic Viral Integration Site 1 Protein
Language	English
Publishing date	2017-07-25
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2064859-5
ISSN	1873-5592 ; 1389-4501
ISSN (online)	1873-5592
ISSN	1389-4501
DOI	10.2174/1389450118666170724165514
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Zs.A 5578: Show issues

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Article ; Online: In Vitro FVIII-Encoding Transgenic Mesenchymal Stem Cells Maintain Successful Coagulation in FVIII-Deficient Plasma Mimicking Hemophilia A

Hemşinlioğlu, Cansu / Aslan, Elif Sibel / Taştan, Cihan / Çakırsoy, Didem / Turan, Raife Dilek / Seyis, Utku / Elek, Muhammer / Sır Karakuş, Gözde / Günaydın, Ömur Selin / Abanuz, Selen / Kançağı, Derya Dilek / Yurtsever, Bulut / Yalçın, Koray / Kasap, Murat / Ovalı, Ercüment

Turkish journal of haematology : official journal of Turkish Society of Haematology

2023 Volume 40, Issue 2, Page(s) 118–124

Abstract: Objective: Hemophilia A is an X-linked recessive bleeding disorder caused by a deficiency of plasma coagulation factor VIII (FVIII), and it accounts for about 80%-85% of all cases of hemophilia. Plasma-derived therapies or recombinant FVIII concentrates ...

Abstract	Objective: Hemophilia A is an X-linked recessive bleeding disorder caused by a deficiency of plasma coagulation factor VIII (FVIII), and it accounts for about 80%-85% of all cases of hemophilia. Plasma-derived therapies or recombinant FVIII concentrates are used to prevent and treat the bleeding symptoms along with FVIII-mimicking antibodies. Recently, the European Medicines Agency granted conditional marketing approval for the first gene therapy for hemophilia A. The aim of this study was to determine the effectiveness of coagulation in correcting FVIII deficiency with FVIII-secreting transgenic mesenchymal stem cells (MSCs). Materials and methods: A lentiviral vector encoding a B domain-deleted FVIII cDNA sequence with CD45R0 truncated (CD45R0t) surface marker was designed to develop a transgenic FVIII-expressing primary cell line by transducing MSCs. The efficacy and functionality of the FVIII secreted from the MSCs was assessed with anti-FVIII ELISA, CD45R0t flow cytometry, FVIII western blot, and mixing test analysis in vitro. Results: The findings of this study showed that the transgenic MSCs maintained persistent FVIII secretion. There was no significant difference in FVIII secretion over time, suggesting stable FVIII expression from the MSCs. The functionality of the FVIII protein secreted in the MSC supernatant was demonstrated by applying a mixing test in coagulation analysis. In the mixing test analysis, FVIII-deficient human plasma products were mixed with either a saline control or FVIII-secreted MSC supernatant. The mean FVIII level of the saline control group was 0.41±0.03 IU/dL, whereas the mean level was 25.41±33.38 IU/dL in the FVIII-secreting MSC supernatant mixed group (p<0.01). The mean activated partial thromboplastin time (aPTT) of the saline control group was 92.69±11.38 s, while in the FVIII-secreting MSC supernatant mixed group, the mean aPTT level decreased to 38.60±13.38 s (p<0.001). Conclusion: The findings of this in vitro study suggest that the new method presented here is promising as a possible treatment for hemophilia A. Accordingly, a study of FVIII-secreting transgenic MSCs will next be initiated in a FVIII-knockout animal model.
MeSH term(s)	Animals ; Humans ; Factor VIII/genetics ; Hemophilia A/genetics ; Hemophilia A/therapy ; Blood Coagulation ; Genetic Therapy/methods ; Mesenchymal Stem Cells/metabolism
Chemical Substances	Factor VIII (9001-27-8)
Language	English
Publishing date	2023-04-06
Publishing country	Turkey
Document type	Journal Article
ZDB-ID	2185903-6
ISSN	1308-5263 ; 1300-7777
ISSN (online)	1308-5263
ISSN	1300-7777
DOI	10.4274/tjh.galenos.2023.2022-0318
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Article ; Online: microRNA 1307 Is a Potential Target for SARS-CoV-2 Infection: An

Arisan, Elif Damla / Dart, D Alwyn / Grant, Guy H / Dalby, Andrew / Kancagi, Derya Dilek / Turan, Raife Dilek / Yurtsever, Bulut / Karakus, Gozde Sir / Ovali, Ercument / Lange, Sigrun / Uysal-Onganer, Pinar

ACS omega

2022 Volume 7, Issue 42, Page(s) 38003–38014

Abstract: microRNAs (miRs) are proposed as critical molecular targets in SARS-CoV-2 infection. Our ... ...

Abstract	microRNAs (miRs) are proposed as critical molecular targets in SARS-CoV-2 infection. Our recent
Language	English
Publishing date	2022-10-11
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c05245
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Article ; Online: Evolving approaches to heart regeneration by therapeutic stimulation of resident cardiomyocyte cell cycle.

Turan, Raife Dilek / Aslan, Galip Servet / Yücel, Doğacan / Döğer, Remziye / Kocabaş, Fatih

Anatolian journal of cardiology

2016 Volume 16, Issue 11, Page(s) 881–886

Abstract: Heart has long been considered a terminally differentiated organ. Recent studies, however, have suggested that there is a modest degree of cardiomyocyte (CM) turnover in adult mammalian heart, albeit not sufficient for replacement of lost CMs following ... ...

Abstract	Heart has long been considered a terminally differentiated organ. Recent studies, however, have suggested that there is a modest degree of cardiomyocyte (CM) turnover in adult mammalian heart, albeit not sufficient for replacement of lost CMs following cardiac injuries. Cardiac regeneration studies in various model organisms including zebrafish, newt, and more recently in neonatal mouse, have demonstrated that CM dedifferentiation and concomitant proliferation play important roles in replacement of lost CMs and restoration of cardiac contractility. Further studies with neonatal cardiac regeneration mouse model suggested that major source of new CMs is existing CMs, with the possibility of involvement of cardiac stem cells. Numerous studies have now been conducted on induction of cardiac regeneration and have identified various cardiogenic factors, cardiogenic micro ribonucleic acid and cardiogenic small molecules. This report is a review of studies regarding generation of CM and prospects for application.
MeSH term(s)	Animals ; Cell Cycle ; Cell Proliferation ; Heart ; Mice ; Myocytes, Cardiac ; Regeneration ; Salamandridae ; Zebrafish
Language	English
Publishing date	2016-11-21
Publishing country	Turkey
Document type	Journal Article ; Review
ZDB-ID	2278670-3
ISSN	2149-2271 ; 2149-2263
ISSN (online)	2149-2271
ISSN	2149-2263
DOI	10.14744/AnatolJCardiol.2016.7245
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Article ; Online: Development of Small Molecule MEIS Inhibitors that modulate HSC activity.

Turan, Raife Dilek / Albayrak, Esra / Uslu, Merve / Siyah, Pinar / Alyazici, Lamia Yazgi / Kalkan, Batuhan Mert / Aslan, Galip Servet / Yucel, Dogacan / Aksoz, Merve / Tuysuz, Emre Can / Meric, Neslihan / Durdagi, Serdar / Gulbas, Zafer / Kocabas, Fatih

Scientific reports

2020 Volume 10, Issue 1, Page(s) 7994

Abstract: Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This ... ...

Abstract	Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34
MeSH term(s)	Amino Acid Sequence ; Animals ; Biomarkers ; Bone Marrow Cells ; Cell Proliferation ; Drug Development ; Drug Evaluation, Preclinical ; Flow Cytometry ; Genes, Reporter ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Mesenchymal Stem Cells/drug effects ; Mesenchymal Stem Cells/metabolism ; Mice ; Mice, Knockout ; Models, Molecular ; Myeloid Ecotropic Viral Integration Site 1 Protein/antagonists & inhibitors ; Myeloid Ecotropic Viral Integration Site 1 Protein/chemistry ; Protein Conformation ; Small Molecule Libraries ; Structure-Activity Relationship
Chemical Substances	Biomarkers ; Myeloid Ecotropic Viral Integration Site 1 Protein ; Small Molecule Libraries
Language	English
Publishing date	2020-05-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-64888-3
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Article ; Online: Preliminary Report of the Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application

Erdoğan, Ebru / Yalçın, Koray / Hemşinlioğlu, Cansu / Sezgin, Aslıhan / Seyis, Utku / Kançağı, Derya Dilek / Taştan, Cihan / Yurtsever, Bulut / Turan, Raife Dilek / Çakırsoy, Didem / Abanuz, Selen / Sır Karakuş, Gözde / Elek, Muhammer / Bekoz, Hüseyin Saffet / Gemici, Ali İhsan / Sargın, Deniz / Arat, Mutlu / Ferhanoğlu, Burhan / Pekgüç, Ebru /

Örnek, Serdar / Büyüktaş, Deram / Birgen, Nur / Ratip, Siret / Ovalı, Ercüment

Turkish journal of haematology : official journal of Turkish Society of Haematology

2022 Volume 39, Issue 3, Page(s) 206–210

Abstract: Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability ... ...

Abstract	Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented. Materials and methods: A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study. Results: Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up. Conclusion: Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.
MeSH term(s)	Antigens, CD19 ; Humans ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Lymphoma, Non-Hodgkin/therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/therapeutic use ; Receptors, Chimeric Antigen ; Turkey/epidemiology
Chemical Substances	Antigens, CD19 ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
Language	English
Publishing date	2022-07-18
Publishing country	Turkey
Document type	Clinical Trial ; Journal Article
ZDB-ID	2185903-6
ISSN	1308-5263 ; 1300-7777
ISSN (online)	1308-5263
ISSN	1300-7777
DOI	10.4274/tjh.galenos.2022.2022.0193
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Article ; Online: c-Myc Inhibitor 10074-G5 Induces Murine and Human Hematopoietic Stem and Progenitor Cell Expansion and HDR Modulator Rad51 Expression.

Aksoz, Merve / Albayrak, Esra / Aslan, Galip Servet / Turan, Raife Dilek / Alyazici, Lamia Yazgi / Siyah, Pınar / Tuysuz, Emre Can / Canikyan, Serli / Yucel, Dogacan / Meric, Neslihan / Gulbas, Zafer / Sahin, Fikrettin / Kocabas, Fatih

Current cancer drug targets

2018 Volume 19, Issue 6, Page(s) 479–494

Abstract: Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence.: Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant ... ...

Abstract	Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Methods and results: Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclindependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression. Conclusion: These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Apoptosis/drug effects ; Cell Culture Techniques ; Cell Cycle/drug effects ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Lysine/analogs & derivatives ; Lysine/pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Nitric Oxide Synthase/antagonists & inhibitors ; Oxadiazoles/pharmacology ; Proto-Oncogene Proteins c-myc/antagonists & inhibitors ; Rad51 Recombinase/biosynthesis ; Rad51 Recombinase/genetics ; Rad51 Recombinase/metabolism ; Small Molecule Libraries/pharmacology ; Taurochenodeoxycholic Acid/pharmacology
Chemical Substances	10074-G5 ; Antiviral Agents ; Enzyme Inhibitors ; N(6)-(1-iminoethyl)lysine ; Oxadiazoles ; Proto-Oncogene Proteins c-myc ; Small Molecule Libraries ; Taurochenodeoxycholic Acid (516-35-8) ; tauroursodeoxycholic acid (60EUX8MN5X) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Rad51 Recombinase (EC 2.7.7.-) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2018-09-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2064824-8
ISSN	1873-5576 ; 1568-0096
ISSN (online)	1873-5576
ISSN	1568-0096
DOI	10.2174/1568009618666180905100608
Database	MEDical Literature Analysis and Retrieval System OnLINE

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