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Effect of suramin on squamous differentiation and apoptosis in three human non-small cell lung cancer cell lines (1996)

Lokshin, Anna ; Levitt, Mark L.

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 63 (1996), S. 186-197

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ISSN: 0730-2312

Keywords: suramin ; apoptosis ; squamous differentiation ; lung cancer ; Life Sciences ; Molecular Cell Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Non-small cell lung cancer (NSCLC) is fatal in approximately 90% of all cases due to the failure of systemic therapy, secondary to resistance to chemotherapy. In such malignancies new therapeutic paradigms are needed. One such approach takes advantage of normal physiologic growth regulatory mechanisms, such as terminal cellular differentiation or apoptosis. Suramin, as an antineoplastic drug, has shown efficacy in the treatment of prostate cancer and is capable of promoting differentiation in several human cancer cell lines. Little is known about the differentiating effects of suramin in lung cancer. In the present investigation we evaluated the ability of suramin to induce cross-linked envelope (CLE) formation, as a common marker for squamous differentiation and apoptosis, in three representative human non-small cell lung cancer cell lines: NCI-H226 (squamous), NCI-H358 (bronchoalveolar [adenocarcinoma]), and NCI-H596 (adenosquamous). Among agents that we have tested, suramin demonstrated the unique ability to induce spontaneous CLE formation in the two cell lines with squamous features, NCI-H226 and NCI-H596. Suramin induced CLE formation was accompanied by DNA fragmentation, a marker for apoptosis, in NCI-H596 and NCI-H358, but not in NCI-H226. Stimulation of CLE formation by suramin correlated with the rapid induction of both type II transglutaminase (TG) activity and involucrin expression. These parameters were protein synthesis independent, suggesting posttranslational mechanisms of suramin activity. Induction of differentiation/apoptosis markers by suramin did not correlate with its effect on growth. Modulation of signal transduction is a likely candidate mechanism for suramin activity in lung cancer. The relationship between growth, squamous differentiation, and apoptosis is considered. © 1996 Wiley-Liss, Inc.

Additional Material: 7 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/jcb.240630514

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Temporal reliability of cytokines and growth factors in EDTA plasma (2010)

Clendenen, Tess V ; Arslan, Alan A ; Lokshin, Anna E ; [et al.]

BioMed Central

In: BMC Research Notes. 2010; 3(1): 302. Published 2010 Nov 13. doi: 10.1186/1756-0500-3-302.

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Publication Date: 2010-11-13

Electronic ISSN: 1756-0500

Topics: Biology , Medicine

Published by BioMed Central

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Role of STAT1 Expression during Graft-Versus-Host Disease (GVHD) in the Gastrointestinal Tract: Association with Lamina Propria Cell Infiltration and Tissue Cytokine/Chemokine Expression. (2006)

Ziegler, Judy A. ; Lokshin, Anna ; Sepulveda, Antonia R. ; [et al.]

American Society of Hematology

In: Blood. 2006; 108(11): 3175-3175. Published 2006 Nov 16. doi: 10.1182/blood.v108.11.3175.3175.

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Publication Date: 2006-11-16

Description: The role of the IFN-g in the development of GVHD remains enigmatic. Whereas it has been shown that GVHD can occur in the absence of IFN-g, there are partially contradicting results how IFN-g can modulate GVHD. Thus, it has been suggested that blocking IFN-g might ameliorate gut GVHD in rodent BMT models and its direct cytopathic effects in human ex vivo skin explant models. However, there is also data supporting the notion that IFN-g is important for limiting GVHD by induction of activation induced cell death (AICD) in donor T cells. Furthermore, it has been demonstrated in preclinical BMT models that IFN-g may accelerate or mitigate GVHD depending on the conditioning intensity. We have recently demonstrated that mitigation of GVHD by treatment with the Histone deacetylase Inhibitor (HDACi) suberonylanilide hydroxamic acid (SAHA) is associated with early downregulation of STAT1 phosphorylation in the spleen and host epithelial GVHD target organs. To further understand the role of STAT1 in the development of GVHD we studied STAT1 and p-STAT1 (Tyr701) expression by immunohistochemistry in the GVHD target organs liver, small bowel and colon following induction of GVHD and correlated these findings with the presence of lamina propria (LP) lymphocytes, typical features of GVHD-induced tissue damage (crypt cell apoptosis, crypt regeneration) and expression of tissue cytokines/chemokines. GVHD was induced in the fully MHC mismatched BALB/c to B6 strain combination following lethal irradiation with 975 rad and animals were sacrificed on days +1, +3 and +6. As detected by western blots p-STAT1 expression became detectable on day +1 in the spleen and on days +3 in the liver, small bowel and colon. Compared to untreated controls immunohistochemical p-STAT1 staining became apparent on day +3 post-BMT in the small bowel and colon of syngeneic controls and GVHD animals. In syngeneic controls p-STAT1 expression decreased again on day +6. In contrast, a further significant increase in p-STAT1 staining was observed in animals with GVHD in the colon and small bowel on day +6. In the colon this significant increase in crypt cell p-STAT1 staining was associated with the presence of LP infiltrating lymphocytes and coincided with the maximal features of tissue damage (luminal sloughing, crypt destruction and crypt apoptosis). In line with these results IFN-g protein expression became detectable in colon tissue lysates on day +6 supporting the role of IFN-g producing infiltrating donor T cells in causing STAT1 activation and tissue damage. We conclude that in comparison to untreated controls STAT1 activation can be observed in the colon and small bowel starting on day +3 in animals with GVHD and syngeneic controls. Whereas pSTAT1 staining peaks at day +3 in syngeneic controls and declines thereafter, maximal STAT1 activation occurs in GVHD animals on day +6, coincides with detectable IFN-g expression and is accompanied by LP infiltration and features of severe GVHD-related tissue damage. To fully understand the role of IFN-g in the development of gut GVHD further studies are warranted to delineate the role of STAT1 dependent and independent signaling pathways in the development of GVHD.

Print ISSN: 0006-4971

Electronic ISSN: 1528-0020

Topics: Biology , Medicine

Published by American Society of Hematology

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A Novel Multiplex Drug Screening Assay for Identification of Potential Compounds with Anti-Myeloma Activity from a Library of 1120 Drugs. (2006)

Feng, Rentian ; Lokshin, Anna ; Gorelik, Elieser ; [et al.]

American Society of Hematology

In: Blood. 2006; 108(11): 3403-3403. Published 2006 Nov 16. doi: 10.1182/blood.v108.11.3403.3403.

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Publication Date: 2006-11-16

Description: The majority of drug screening assays are aimed at selection of compounds that affect proliferation or survival of myeloma cells. However, this approach might fail to identify compounds with a potent therapeutic activity that are unable to directly inhibit tumor cell proliferation in vitro but might have potent anti-tumor activity in vivo by targeting the microenvironment of the myeloma cell. For this purpose we used a Multiplex drug-screening assay (MDSA) to identify compounds with potential anti-myeloma activity from a library of 1120 compounds provided by the Multiple Myeloma Research Foundation (MMRF). MDSA is based on use of the Luminex technology (LabMAP Multianalyte Profiling), and testing various myeloma producing factors (MPFs), such as cytokines, chemokines and growth factors that are important for myeloma cell proliferation and survival. The multiple myeloma cell lines MM1.S, RPMI-8226, and IM9 were tested for their capacity to secrete the full set of 31 cytokines, chemokines and growth factors. RPMI-8226 was selected for MDSA due to its high capacity to secrete MPFs (IL-8, VEGF, MCP-1, MIP-1α, MIP-1β, IP10, RANTES and SIL-6R). RPMI-8226 cells were treated with 10 10−6M of each compound (first screening phase) and 1 10−6M (secondary screening), and supernatants from 72-hour cultures were analyzed. The criterion of effective drugs for each cytokine was set up as the ability to inhibit or stimulate MPFs (exceed +/− 1.5 mean value of non-treated control). The resulting data on the drugs were graded by the degree to which they caused inhibition or stimulation of all MPFs (greater than 50% and greater than 90%). A total of 205 of the 1,120 candidates were picked out from the first screening at 10 10−6M. Results from the second analysis (at 1 10−6M) indicated that 14 compounds achieved inhibition of all MPFs and dequalinium dichloride manifested the strongest inhibition of all MPFs. Forty drugs were able to selectively inhibit certain MPFs at levels that exceeded 50% and 14 drugs inhibited MPFs by 90%. With respect to stimulation of cytokine secretion, a total of 39 compounds demonstrated selective stimulation of some MPFs and three drugs (amethopterin (R, S), etoposide, and lasalocid sodium salt) induced stimulation at the level of 90% or greater. Overall, MDSA is a powerful high throughput screening assay to analyze compounds with inhibitory or stimulatory effects on cytokines, chemokines and growth factors that are involved in the pathogenesis of multiple myeloma. Potent compounds identified in this study warrant further investigation for their anti-myeloma effects in vitro and in vivo.

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Electronic ISSN: 1528-0020

Topics: Biology , Medicine

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Chemokine Profiling in Patients with Graft Versus Host Disease (GVHD) Following Allogeneic Blood Stem Cell Transplantation. (2006)

Ziegler, Judy A. ; Lokshin, Anna ; Lentzsch, Suzanne ; [et al.]

American Society of Hematology

In: Blood. 2006; 108(11): 2877-2877. Published 2006 Nov 16. doi: 10.1182/blood.v108.11.2877.2877.

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Publication Date: 2006-11-16

Description: Development of GVHD following allogeneic blood stem cell or bone marrow transplantation (BMT) is dependent on the immunogenetic disparity between donor and host, subsequent alloactivation and the inflammatory reaction occurring secondary to conditioning regimen-induced tissue damage. The inflammatory response occurring early following conditioning therapy is thought to be particularly crucial for the subsequent development of GVHD as it occurs in response to tissue damage and is amplified by the alloresponse. Chemokines are predominantly small molecules (8–14 kd) that bind to a family of heterotrimeric G-protein-coupled receptors with a seven-transmembrane-spanning serpentine structure and play an important role in leukocyte trafficking and are thought to be involved in tissue infiltration during GVHD. Reports from several investigators using murine model have demonstrated the relevance of distinct chemokines in the pathogenesis of GVHD. Furthermore, we have recently demonstrated that conditioning intensity and genetic host factors influence the tissue and systemic expression of chemokines during the early course of GVHD in rodent BMT models. However, the pathobiologic relevance of chemokines expression at later time points during GVHD and in human GVHD is so far unclear. Using luminex multiplex assays we studied the sera of patients, who had undergone peripheral blood stem transplantation from an allogeneic HLA matched sibling or matched unrelated donor in order to determine the chemokine profiles during GVHD. In addition to the most relevant cytokines/cytokine receptors (IL-1a, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IFN-a, IFN-g, GM-CSF, IL-12 (p40), IL-13, IL-15, IL17, TNF-alpha, TNF-RI, TNF-RII, DR5, FGF-b, VEGF, HGF, IL-1Ra, sIL-2R and sIL-6R), we analyzed the serum expression of CCL2, CCL3, CCL4, CCL5, CCL11, CXCL9, and CXCL10. Patients with acute GVHD of the gut (n=8), patients without GVHD (n = 4) and patients with chronic GVHD (n=4) were studied. Patients with acute/chronic GVHD had significantly elevated levels of CCL3 (90 pg/ml vs. 58 pg/ml, p= 0.004) and CCL11 (167pg/ml vs. 93pg/ml) compared to controls patients without GVHD. Patients with acute GVHD of the gut had also markedly elevated CXCL10, CCL4 levels although not reaching statistical significance. In addition, patients with acute or chronic GVHD were found to have significantly elevated serum levels of HGF, IL-1Ra, and TNF-RI. In conclusion we are able to demonstrate that CCL3 appears to be the most prominent chemokine to be elevated in the serum of patients with a/cGVHD supporting results obtained in preclinical BMT models. Given the complex and frequently contradictory preclinical results, further studies are warranted to confirm our findings in larger cohorts of patients and to delineate whether targeting CCL3 or one of its receptor (CCR1 or CCR5) might prove beneficial for the treatment of GVHD.

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Topics: Biology , Medicine

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Protein-Based Identification of Inflammatory Signaling Pathways in Graft-Versus-Host-Disease (GVHD): Evidence for STAT1 Pathway as a Key Regulator in GVHD. (2005)

Li, Cuiling ; Ziegler, Judy ; Leng, Corinna ; [et al.]

American Society of Hematology

In: Blood. 2005; 106(11): 1318-1318. Published 2005 Nov 16. doi: 10.1182/blood.v106.11.1318.1318.

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Publication Date: 2005-11-16

Description: The pathogenesis of GVHD is influenced by the immunogenetic disparities between donor and recipient, the presence of host-derived antigen-presenting cells, the inflammatory reaction in response to conditioning-induced tissue damage and cytokine secretion. Intestinal damage and subsequent translocation of LPS into the circulation have been shown to be central to the subsequent pathogenetic events occurring in development of GVHD. Interfering with this proinflammatory response by targeted therapy might be an attractive new approach for inhibiting the development of GVHD. We have therefore started to comprehensively analyze the inflammatory signaling pathways, which are activated during the induction phase of GVHD in order to identify key molecular regulators of GVHD, which might serve as targets for future therapy. For this purpose GVHD was in induced in the fully MHC-mismatched BALB/c to B6 strain combination following lethal irradiation with 9.5 Gy. Spleens as well as GVHD target organs liver, skin and small bowel and colon were harvested on days 1, 3, and + 6 post-BMT to study activation of JAK-STAT, MAPK, PI3-Kinase and NF-κB signaling transduction pathways. Studies were performed using western blot, multiplex assays for analysis of phoshotyrosine proteins and transcription factor binding activity and also standard gel shift assays. Furthermore, GVHD liver tissue was subjected to microarray gene expression profiling. Most strikingly, in contrast to syngeneic and allogeneic controls induction of GVHD was associated with a strong activation of JAK-STAT pathway as determined by Tyr701-specific STAT1 phosphorylation and also Tyr705-specific STAT3 phosphorylation in the liver and spleen as early as on day +1 post-BMT and remained elevated until day +6 post-BMT. In line with these results we observed a significant increase of STAT1 dependent gene expression (e.g. CXCL10 5.6-fold, IRF7 4.5-fold, CXCL9 4.2-fold) as studied by microarray gene expression profiling in the liver. Furthermore, multiplex DNA-binding and standard gel shift studies in the liver revealed that GVHD led to an increased DNA binding activity of most prominently NF-κB but also AP-2, EGR1 and NF1. In conclusion we provide evidence that induction of GVHD is associated with strong activation of the STAT1 pathway in the spleen and liver as early as on day +1 post-BMT in additon to activation of the NF-κB pathway. Therefore this study might help to identify candidate molecules to create more specific therapies targeting the inflammatory component of GVHD and thus reducing the development of GVHD without mitigating the GVL response.

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Inhibition of Graft-Versus-Host Disease (GVHD) by Histone Deacetylase Inhibitor (HDAC) SAHA Leads to Downregulation of STAT1 Activation. (2005)

Leng, Corinna ; Li, Cuiling ; Ziegler, Judy ; [et al.]

American Society of Hematology

In: Blood. 2005; 106(11): 1311-1311. Published 2005 Nov 16. doi: 10.1182/blood.v106.11.1311.1311.

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Publication Date: 2005-11-16

Description: Histone deacetylase (HDAC) inhibitors have been shown to reduce development of graft versus host disease [GVHD] following allogeneic bone marrow transplantation [BMT]. Administration of the HDAC inhibitor suberonylanilide hydroxamic acid [SAHA] resulted in a significantly reduced GVHD-dependent mortality following fully MHC-mismatched allogeneic BMT. Median Survival Time (MST) for vehicle and SAHA-treated mice were 7.5 days and 38 days respectively. However, SAHA treatment did not affect T cell activation nor T cell expansion in vitro and in vivo as determined by MLR assays, phenotypic analysis of donor T cells with regard to expression of the CD25 activation antigen and calculation of donor CD4+ and CD8+ T cell numbers on days +3 and +6 post-BMT. Thus, SAHA treatment was not able to inhibit the strong upregulation of CD25 antigen on CD8+ T cells observed during induction of GVHD on days +3 and +6 post-BMT. We therefore focused on the effects of SAHA treatment on efferent immune effects including cytokine secretion and intracellular signaling events in vitro and in vivo following GVHD induction. SAHA treatment broadly inhibited lipopolysaccharide [LPS] and allo-antigen-induced cytokine/chemokine secretion in vitro like MIP-1-α, IP-10, IFN-γ, TNF-α and IL-6 and led also to a significant decrease in IFN-γ and TNF-α levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and allo-activation in vitro. Furthermore, analysis of liver tissue and spleens from SAHA-treated animals with GVHD showed a significant decrease in phosphorylated STAT1. In contrast SAHA treatment had only moderate effects on p38 or ERK1,2 Mitogen-activated Protein Kinase (MAPK) pathway underscoring the relevance of the inhibition of the STAT1 pathway. In conclusion, GVHD is associated with a strong induction of phosphorylation of STAT1 in the liver and spleen and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of pSTAT1 and modulation of the inflammatory cytokine milieu during the efferent immune response.

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Topics: Biology , Medicine

Published by American Society of Hematology

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