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Article ; Online: A model for overcoming challenges in academic pediatric medical device innovation.

Fischer, Gwenyth A / Wells, Sandra M / Rebuffoni, Jodi F / Peterson, Brittni M / LeBien, Tucker W

Journal of clinical and translational science

2019 Volume 3, Issue 1, Page(s) 5–11

Abstract: Technological advancements in medical devices developed for adults far outpace the development of technologies designed for pediatric patients in the USA and other countries. This technology lag was previously reflected in a lack of pediatric-specific ... ...

Abstract	Technological advancements in medical devices developed for adults far outpace the development of technologies designed for pediatric patients in the USA and other countries. This technology lag was previously reflected in a lack of pediatric-specific innovation within our academic institution. To address the institutional deficit of device innovation around pediatric patients, we formed unique partnerships both within our university and extending to the medical device industry, and developed novel programmatic approaches. The Pediatric Device Innovation Consortium (PDIC) bridges the medical device community and the University of Minnesota. Since 2014, the PDIC has supported 22 pediatric medical technology innovation projects, provided funds totaling more than $500,000, licensed two technologies, and advanced two technologies to patient use. Here, we describe the PDIC model and method, the PDIC approach to common challenges that arise in the development of small-market medical technologies at an academic institution, and iterations to our collaborative, multidisciplinary approach that have matured throughout our experience. The PDIC model continues to evolve to reflect the special needs of innovation for smaller markets and the unique role of clinician innovators. Our approach serves as a successful model for other institutions interested in creating support mechanisms for pediatric or small-market technology development.
Language	English
Publishing date	2019-07-04
Publishing country	England
Document type	Journal Article
ISSN	2059-8661
ISSN (online)	2059-8661
DOI	10.1017/cts.2019.370
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Novel team-based approaches to advance academic translational research.

Wells, Sandra M / Rebuffoni, Jodi Fenlon / LeBien, Tucker W

Clinical and translational science

2014 Volume 7, Issue 6, Page(s) 427–429

MeSH term(s)	Academic Medical Centers ; Cooperative Behavior ; Humans ; Translational Medical Research
Language	English
Publishing date	2014-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.12211
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Article: Arginine: an unusual dietary requirement of pre-B lymphocytes?

LeBien, Tucker W

The Journal of clinical investigation

2002 Volume 110, Issue 10, Page(s) 1411–1413

MeSH term(s)	Animals ; Arginine/immunology ; Arginine/metabolism ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Homeostasis ; Humans ; Mice ; Models, Biological
Chemical Substances	Arginine (94ZLA3W45F)
Language	English
Publishing date	2002-11
Publishing country	United States
Document type	Comment ; Journal Article ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI17210
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: B lymphocytes: how they develop and function.

LeBien, Tucker W / Tedder, Thomas F

Blood

2008 Volume 112, Issue 5, Page(s) 1570–1580

Abstract: The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T ... ...

Abstract	The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries.
MeSH term(s)	Animals ; Antigens, Differentiation, B-Lymphocyte/history ; Antigens, Differentiation, B-Lymphocyte/metabolism ; Autoimmune Diseases/history ; Autoimmune Diseases/immunology ; B-Lymphocyte Subsets/cytology ; B-Lymphocyte Subsets/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; Cell Differentiation ; Cell Membrane/immunology ; History, 20th Century ; History, 21st Century ; Humans ; Immunologic Deficiency Syndromes/history ; Immunologic Deficiency Syndromes/immunology ; Leukemia/history ; Leukemia/immunology ; Lymphoma/history ; Lymphoma/immunology ; Mice ; Models, Immunological
Chemical Substances	Antigens, Differentiation, B-Lymphocyte
Language	English
Publishing date	2008-08-22
Publishing country	United States
Document type	Historical Article ; Journal Article ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2008-02-078071
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Article: IL-7 activates the phosphatidylinositol 3-kinase/AKT pathway in normal human thymocytes but not normal human B cell precursors.

Johnson, Sonja E / Shah, Nisha / Bajer, Anna A / LeBien, Tucker W

Journal of immunology (Baltimore, Md. : 1950)

2008 Volume 180, Issue 12, Page(s) 8109–8117

Abstract: IL-7 signaling culminates in different biological outcomes in distinct lymphoid populations, but knowledge of the biochemical signaling pathways in normal lymphoid populations is incomplete. We analyzed CD127/IL-7Ralpha expression and function in normal ( ...

Abstract	IL-7 signaling culminates in different biological outcomes in distinct lymphoid populations, but knowledge of the biochemical signaling pathways in normal lymphoid populations is incomplete. We analyzed CD127/IL-7Ralpha expression and function in normal (nontransformed) human thymocytes, and human CD19(+) B-lineage cells purified from xenogeneic cord blood stem cell/MS-5 murine stromal cell cultures, to further clarify the role of IL-7 in human B cell development. IL-7 stimulation of CD34(+) immature thymocytes led to phosphorylation (p-) of STAT5, ERK1/2, AKT, and glycogen synthase kinase-3 beta, and increased AKT enzymatic activity. In contrast, IL-7 stimulation of CD34(-) thymocytes (that included CD4(+)/CD8(+) double-positive, and CD4(+) and CD8(+) single-positive cells) only induced p-STAT5. IL-7 stimulation of CD19(+) cells led to robust induction of p-STAT5, but minimal induction of p-ERK1/2 and p-glycogen synthase kinase-3 beta. However, CD19(+) cells expressed endogenous p-ERK1/2, and when rested for several hours following removal from MS-5 underwent de-phosphorylation of ERK1/2. IL-7 stimulation of rested CD19(+) cells resulted in robust induction of p-ERK1/2, but no induction of AKT enzymatic activity. The use of a specific JAK3 antagonist demonstrated that all IL-7 signaling pathways in CD34(+) thymocytes and CD19(+) B-lineage cells were JAK3-dependent. We conclude that human CD34(+) thymocytes and CD19(+) B-lineage cells exhibit similarities in activation of STAT5 and ERK1/2, but differences in activation of the PI3K/AKT pathway. The different induction of PI3K/AKT may at least partially explain the different requirements for IL-7 during human T and B cell development.
MeSH term(s)	Adult ; Animals ; B-Lymphocyte Subsets/enzymology ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; Cell Line, Tumor ; Cell Lineage/immunology ; Cell Proliferation ; Cell Survival/immunology ; Cells, Cultured ; Embryonic Stem Cells/enzymology ; Embryonic Stem Cells/immunology ; Enzyme Activation/immunology ; Enzyme Induction/immunology ; Humans ; Interleukin-7/physiology ; Interleukin-7 Receptor alpha Subunit/biosynthesis ; Interleukin-7 Receptor alpha Subunit/genetics ; Mice ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositol 3-Kinases/physiology ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/biosynthesis ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-akt/physiology ; Signal Transduction/drug effects ; Signal Transduction/immunology ; Stem Cells/enzymology ; Stem Cells/immunology ; Stem Cells/metabolism ; Thymus Gland/cytology ; Thymus Gland/enzymology ; Thymus Gland/immunology
Chemical Substances	IL7 protein, human ; Interleukin-7 ; Interleukin-7 Receptor alpha Subunit ; Protein Kinase Inhibitors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2008-05-20
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.180.12.8109
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Article: Enhancement of stress-induced apoptosis in B-lineage cells by caspase-9 inhibitor.

Shah, Nisha / Asch, Rebecca J / Lysholm, Alana S / Lebien, Tucker W

Blood

2004 Volume 104, Issue 9, Page(s) 2873–2878

Abstract: We have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in ...

Abstract	We have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in mitochondrial transmembrane potential and an increase in annexin V binding. Unexpectedly, the caspase-9 inhibitor (C9i) benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethylketone enhanced the appearance of apoptotic cells within 8 hours following removal of BLIN cells from fibroblast monolayers. C9i enhancement of apoptosis was dose dependent and did not occur with irreversible inhibitors of caspases-2, -3, -6, and -8. C9i also enhanced apoptosis in cord blood-derived CD19(+) B-lineage cells (but not myeloid cells) removed from murine stromal cells. Longer exposure (> 18 hours) to C9i culminated in apoptosis in a panel of B-lineage acute lymphoblastic leukemia (ALL) cell lines in the presence or absence of fibroblast monolayers, as well as in 2 proliferating leukemic cell lines (RAMOS and CEM). BLIN-4L cells made deficient in caspase-9 by RNA interference exhibited no resistance to apoptotic signals and actually showed increased apoptotic sensitivity to staurosporine. These collective results suggest that a 4-amino acid caspase inhibitor of caspase-9 can promote apoptosis and that at least some types of apoptotic pathways in B-lineage ALL do not require caspase-9.
MeSH term(s)	Animals ; Apoptosis/drug effects ; B-Lymphocytes/drug effects ; B-Lymphocytes/pathology ; Burkitt Lymphoma/pathology ; Caspase 9 ; Caspase Inhibitors ; Cell Line, Tumor ; Coculture Techniques ; Cysteine Proteinase Inhibitors/pharmacology ; Fibroblasts/cytology ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Humans ; Mice ; Oligopeptides/pharmacology ; Stress, Physiological/pathology
Chemical Substances	Caspase Inhibitors ; Cysteine Proteinase Inhibitors ; Oligopeptides ; benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone ; CASP9 protein, human (EC 3.4.22.-) ; Casp9 protein, mouse (EC 3.4.22.-) ; Caspase 9 (EC 3.4.22.-)
Language	English
Publishing date	2004-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2003-10-3720
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Article: Murine and human IL-7 activate STAT5 and induce proliferation of normal human pro-B cells.

Johnson, Sonja E / Shah, Nisha / Panoskaltsis-Mortari, Angela / LeBien, Tucker W

Journal of immunology (Baltimore, Md. : 1950)

2005 Volume 175, Issue 11, Page(s) 7325–7331

Abstract: The role of IL-7 in lymphoid development and T cell homeostasis has been extensively documented. However, the role of IL-7 in human B cell development remains unclear. We used a xenogeneic human cord blood stem cell/murine stromal cell culture to study ... ...

Abstract	The role of IL-7 in lymphoid development and T cell homeostasis has been extensively documented. However, the role of IL-7 in human B cell development remains unclear. We used a xenogeneic human cord blood stem cell/murine stromal cell culture to study the development of CD19+ B-lineage cells expressing the IL-7R. CD34+ cord blood stem cells were cultured on the MS-5 murine stromal cell line supplemented with human G-CSF and stem cell factor. Following an initial expansion of myeloid/monocytoid cells within the initial 2 wk, CD19+/pre-BCR- pro-B cells emerged, of which 25-50% expressed the IL-7R. FACS-purified CD19+/IL-7R+ cells were larger and, when replated on MS-5, underwent a dose-dependent proliferative response to exogenous human IL-7 (0.01-10.0 ng/ml). Furthermore, STAT5 phosphorylation was induced by the same concentrations of human IL-7. CD19+/IL-7R- cells were smaller and did not proliferate on MS-5 after stimulation with IL-7. In a search for cytokines that promote human B cell development in the cord blood stem cell/MS-5 culture, we made the unexpected finding that murine IL-7 plays a role. Murine IL-7 was detected in MS-5 supernatants by ELISA, recombinant murine IL-7 induced STAT5 phosphorylation in CD19+/IL-7R+ pro-B cells and human B-lineage acute lymphoblastic leukemias, and neutralizing anti-murine IL-7 inhibited development of CD19+ cells in the cord blood stem cell/MS-5 culture. Our results support a model wherein IL-7 transduces a replicative signal to normal human B-lineage cells that is complemented by additional stromal cell-derived signals essential for normal human B cell development.
MeSH term(s)	Animals ; Antigens, CD19/immunology ; Antigens, CD19/metabolism ; Antigens, CD34/immunology ; Antigens, CD34/metabolism ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation/immunology ; Cell Lineage/immunology ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Humans ; Interleukin-7/immunology ; Interleukin-7/metabolism ; Mice ; Models, Immunological ; Phosphorylation ; Receptors, Interleukin-7/immunology ; Receptors, Interleukin-7/metabolism ; STAT5 Transcription Factor/immunology ; STAT5 Transcription Factor/metabolism ; Stromal Cells/metabolism
Chemical Substances	Antigens, CD19 ; Antigens, CD34 ; Interleukin-7 ; Receptors, Interleukin-7 ; STAT5 Transcription Factor
Language	English
Publishing date	2005-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.175.11.7325
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Article ; Online: IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells.

Nodland, Sonja E / Berkowska, Magdalena A / Bajer, Anna A / Shah, Nisha / de Ridder, Dick / van Dongen, Jacques J M / LeBien, Tucker W / van Zelm, Menno C

Blood

2011 Volume 118, Issue 8, Page(s) 2116–2127

Abstract: IL-7 is an important cytokine for lymphocyte differentiation. Similar to what occurs in vivo, human CD19⁺ cells developing in human/murine xenogeneic cultures show differential expression of the IL-7 receptor α (IL-7Rα) chain (CD127). We now describe the ...

Abstract	IL-7 is an important cytokine for lymphocyte differentiation. Similar to what occurs in vivo, human CD19⁺ cells developing in human/murine xenogeneic cultures show differential expression of the IL-7 receptor α (IL-7Rα) chain (CD127). We now describe the relationship between CD127 expression/signaling and Ig gene rearrangement. In the present study, < 10% of CD19⁺CD127⁺ and CD19⁺CD127⁻ populations had complete VDJ(H) rearrangements. IGH locus conformation measurements by 3D FISH revealed that CD127⁺ and CD127⁻ cells were less contracted than pediatric BM pro-B cells that actively rearrange the IGH locus. Complete IGH rearrangements in CD127⁺ and CD127⁻ cells had smaller CDR3 lengths and fewer N-nucleotide insertions than pediatric BM B-lineage cells. Despite the paucity of VDJ(H) rearrangements, microarray analysis indicated that CD127⁺ cells resembled large pre-B cells, which is consistent with their low level of Ig light-chain rearrangements. Unexpectedly, CD127⁻ cells showed extensive Ig light-chain rearrangements in the absence of IGH rearrangements and resembled small pre-B cells. Neutralization of IL-7 in xenogeneic cultures led to an increase in Ig light-chain rearrangements in CD127⁺ cells, but no change in complete IGH rearrangements. We conclude that IL-7-mediated suppression of premature Ig light-chain rearrangement is the most definitive function yet described for IL-7 in human B-cell development.
MeSH term(s)	Animals ; Antigens, CD19/metabolism ; Cell Differentiation/immunology ; Cell Lineage/immunology ; Coculture Techniques ; DNA Nucleotidylexotransferase/metabolism ; Fetal Blood/cytology ; Fetal Blood/immunology ; Gene Expression Profiling ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Gene Rearrangement, B-Lymphocyte, Light Chain ; Humans ; Interleukin-7/metabolism ; Interleukin-7 Receptor alpha Subunit/metabolism ; Mice ; Phenotype ; Precursor Cells, B-Lymphoid/cytology ; Precursor Cells, B-Lymphoid/immunology ; Signal Transduction
Chemical Substances	Antigens, CD19 ; IL7 protein, human ; Interleukin-7 ; Interleukin-7 Receptor alpha Subunit ; DNA Nucleotidylexotransferase (EC 2.7.7.31)
Language	English
Publishing date	2011-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2010-08-302513
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Article ; Online: Stable gene transfer and expression in cord blood-derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system.

Xue, Xingkui / Huang, Xin / Nodland, Sonja E / Mátés, Lajos / Ma, Linan / Izsvák, Zsuzsanna / Ivics, Zoltán / LeBien, Tucker W / McIvor, R Scott / Wagner, John E / Zhou, Xianzheng

Blood

2009 Volume 114, Issue 7, Page(s) 1319–1330

Abstract: Here we report stable gene transfer in cord blood-derived CD34(+) hematopoietic stem cells using a hyperactive nonviral Sleeping Beauty (SB) transposase (SB100X). In colony-forming assays, SB100X mediated the highest efficiency (24%) of stable Discosoma ... ...

Abstract	Here we report stable gene transfer in cord blood-derived CD34(+) hematopoietic stem cells using a hyperactive nonviral Sleeping Beauty (SB) transposase (SB100X). In colony-forming assays, SB100X mediated the highest efficiency (24%) of stable Discosoma sp red fluorescent protein (DsRed) reporter gene transfer in committed hematopoietic progenitors compared with both the early-generation hyperactive SB11 transposase and the piggyBac transposon system (1.23% and 3.8%, respectively). In vitro differentiation assays further demonstrated that SB100X-transfected CD34(+) cells can develop into DsRed(+) CD4(+)CD8(+) T (3.17%-21.84%; median, 7.97%), CD19(+) B (3.83%-18.66%; median, 7.84%), CD56(+)CD3(-) NK (3.53%-79.98%; median, 7.88%), and CD33(+) myeloid (7.59%-15.63%; median, 9.48%) cells. SB100X-transfected CD34(+) cells achieved approximately 46% engraftment in NOD-scid IL2gammac(null) (NOG) mice. Twelve weeks after transplantation, 0.57% to 28.96% (median, 2.79%) and 0.49% to 34.50% (median, 5.59%) of total human CD45(+) cells in the bone marrow and spleen expressed DsRed, including CD19(+) B, CD14(+) monocytoid, and CD33(+) myeloid cell lineages. Integration site analysis revealed SB transposon sequences in the human chromosomes of in vitro differentiated T, B, NK, and myeloid cells, as well as in human CD45(+) cells isolated from bone marrow and spleen of transplanted NOG mice. Our results support the continuing development of SB-based gene transfer into human hematopoietic stem cells as a modality for gene therapy.
MeSH term(s)	Animals ; Antigens, CD34 ; Antigens, Differentiation/genetics ; Antigens, Differentiation/metabolism ; Cell Differentiation/genetics ; Cord Blood Stem Cell Transplantation ; DNA Transposable Elements ; Female ; Fetal Blood ; Gene Expression ; Gene Transfer Techniques ; Genetic Therapy/methods ; Graft Survival/genetics ; Hematopoietic Stem Cells ; Humans ; Luminescent Proteins/biosynthesis ; Luminescent Proteins/genetics ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Time Factors ; Transplantation, Heterologous ; Red Fluorescent Protein
Chemical Substances	Antigens, CD34 ; Antigens, Differentiation ; DNA Transposable Elements ; Luminescent Proteins
Language	English
Publishing date	2009-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2009-03-210005
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Article ; Online: Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria.

Hermanson, David / Addo, Sadiya N / Bajer, Anna A / Marchant, Jonathan S / Das, Sonia Goutam Kumar / Srinivasan, Balasubramanian / Al-Mousa, Fawaz / Michelangeli, Francesco / Thomas, David D / Lebien, Tucker W / Xing, Chengguo

Molecular pharmacology

2009 Volume 76, Issue 3, Page(s) 667–678

Abstract: HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog ... ...

Abstract	HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog of HA 14-1 (sHA 14-1). The current study characterizes its mode of action. Because of the antiapoptotic function of Bcl-2 family proteins on the endoplasmic reticulum (ER) and mitochondria, the effect of sHA 14-1 on both organelles was evaluated. sHA 14-1 induced ER calcium release in human leukemic cells within 1 min, followed by induction of the ER stress-inducible transcription factor ATF4. Similar kinetics and stronger intensity of ER calcium release were induced by the sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, accompanied by similar kinetics and intensity of ATF4 induction. sHA 14-1 directly inhibited SERCA enzymatic activity but had no effect on the inositol triphosphate receptor. Evaluation of the mitochondrial pathway showed that sHA 14-1 triggered a loss of mitochondrial transmembrane potential (Delta psi m) and weak caspase-9 activation, whereas thapsigargin had no effect. (R)-4-(3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-3-nitrobenzenesulfonamide (ABT-737), a well established small-molecule Bcl-2 antagonist, rapidly induced loss of Delta psi m and caspase-9 activation but had no effect on the ER. The pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone had some protective effect on sHA 14-1-induced cell death. These collective results suggest a unique dual targeting mechanism of sHA 14-1 on the apoptotic resistance machinery of tumor cells that includes antiapoptotic Bcl-2 family proteins and SERCA proteins.
MeSH term(s)	Apoptosis ; Benzopyrans/chemistry ; Benzopyrans/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Humans ; Mitochondria/drug effects ; Mitochondria/metabolism ; Nitriles/pharmacology ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
Chemical Substances	Benzopyrans ; Nitriles ; Proto-Oncogene Proteins c-bcl-2 ; ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate ; ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate ; Sarcoplasmic Reticulum Calcium-Transporting ATPases (EC 3.6.3.8)
Language	English
Publishing date	2009-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/mol.109.055830
Database	MEDical Literature Analysis and Retrieval System OnLINE

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