Koeffler H.P.,Cedars Sinai Medical Center |
Koeffler H.P.,National Cancer Institute of Singapore
Best Practice and Research: Clinical Haematology
Differentiation therapy with all-trans retinoic acid has been a very successful therapeutic strategy in acute promyelocytic leukemia (APL), but the value of differentiation therapy in acute myeloid leukemia (AML) remains to be determined. A number of current treatments, such as tyrosine kinase inhibitors, cytokines, and epigenetic agents, induce differentiation of leukemic cells to some extent, but differentiation is not the main goal of these treatments. Forcing expression of certain transcription factors, such as C/EBP, has also been useful in inducing differentiation in cell lines and in murine models, but an effective way to force expression of these genes in humans is yet to be discovered. © 2010 Elsevier Ltd. All rights reserved. Source
Chen W.,University of the Free State |
Chen W.,Cedars Sinai Medical Center |
Leiter A.,Cedars Sinai Medical Center |
Dong Y.,Cedars Sinai Medical Center |
And 4 more authors.
International Journal of Oncology
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer with a substantial risk of metastasis which causes clinical treatment failure. This study investigated the anti-CSCC effects of a triterpenoid compound, Cucurbitacin B (CuB). Dose-response studies showed that CuB inhibited 50% growth (ED 50) of the CSCC cell lines (SRB1, SRB12, SCC13, COLO16) in liquid culture at 4×10 -7 -10 -5 M. Soft-agar assays demonstrated that nearly all of the CSCC clonogenic cells were inhibited at 10 -7 M CuB. FACS analysis found that the compound (10 -7 M, 48 h) caused G2/M arrest. The CSCC cells underwent profound morphologic changes within 60 min after exposure to CuB (10 -7 M), rounding up and losing their pseudopodia. CuB (10 -7 M) caused prominent multinucleation of the cells after they were pulse-exposed (24 h) to the drug, washed and cultured in normal medium for an additional 24 h. The drug (10 -8-10 -6 M, 3-24 h) decreased levels of CDC2 and cyclin B1 in SRB1 and SRB12 cell lines as seen by Western blot analysis. Migration of SRB1 and SRB12 cells was inhibited by 10 -7 M CuB. Interestingly, CuB synergistically potentiated the anti-proliferative effect of cisplatin in CSCC. In summary, CuB has a prominent anti-proliferative activity on CSCC cells. In vivo studies and clinical trials of this drug should be pursued in CSCC. Source
Ji X.-D.,CAS Shanghai Institutes for Biological Sciences |
Li G.,CAS Shanghai Institutes for Biological Sciences |
Feng Y.-X.,CAS Shanghai Institutes for Biological Sciences |
Zhao J.-S.,CAS Shanghai Institutes for Biological Sciences |
And 10 more authors.
Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attention. Until now, research on EphB3 function in cancer is limited to focusing on tumor suppression by EphB receptors in colorectal cancer. However, its function in other types of cancer remains poorly investigated. In this study, we explored the function of EphB3 in non-small-cell lung cancer (NSCLC). We found that the expression of EphB3 was significantly upregulated in clinical samples and cell lines, and the expression level correlated with the patient pathologic characteristics, including tumor size, differentiation, and metastasis. Overexpression of EphB3 in NSCLC cell lines accelerated cell growth and migration and promoted tumorigenicity in xenografts in a kinase-independent manner. In contrast, down-regulation of EphB3 inhibited cell proliferation and migration and suppressed in vivo tumor growth and metastasis. Furthermore, we showed that silencing of EphB3 inhibited cell growth by reducing DNA synthesis and caspase-8-mediated apoptosis and suppressed cell migration by increasing accumulation of focal adhesion formation. Taken together, our findings suggest that EphB3 provides critical support to the development and progression of NSCLC by stimulating cell growth, migration, and survival, thereby implicating EphB3 as a potential therapeutic target in NSCLC. ©2011 AACR. Source
Gueller S.,Goethe University Frankfurt |
Gueller S.,Cedars Sinai Medical Center |
Goodridge H.S.,Cedars Sinai Medical Center |
Niebuhr B.,University of Hamburg |
And 7 more authors.
Journal of Leukocyte Biology
The M-CSFR (c-Fms) participates in proliferation, differentiation, and survival of macrophages and is involved in the regulation of distinct macrophage functions. Interaction with the ligand M-CSF results in phosphorylation of tyrosine residues on c-Fms, thereby creating binding sites for molecules containing SH2 domains. Lnk is a SH2 domain adaptor protein that negatively regulates hematopoietic cytokine receptors. Here, we show that Lnk binds to c-Fms. Biological and functional effects of this interaction were examined in macrophages from Lnk-deficient (KO) and WT mice. Clonogenic assays demonstrated an elevated number of M-CFUs in the bone marrow of Lnk KO mice. Furthermore, the M-CSF-induced phosphorylation of Akt in Lnk KO macrophages was increased and prolonged, whereas phosphorylation of Erk was diminished. Zymosan-stimulated production of ROS was increased dramatically in a M-CSF-dependent manner in Lnk KO macrophages. Lastly, Lnk inhibited M-CSF-induced migration of macrophages. In summary, we show that Lnk binds to c-Fms and can blunt M-CSF stimulation. Modulation of levels of Lnk in macrophages may provide a unique therapeutic approach to increase innate host defenses. © Society for Leukocyte Biology. Source
Tey J.,National University Hospital Singapore |
Tey J.,National Cancer Institute of Singapore |
Choo B.A.,National Cancer Institute of Singapore |
Leong C.N.,National University Hospital Singapore |
And 10 more authors.
Medicine (United States)
The purpose of this study was to report the outcomes of patients with symptomatic locally advanced/recurrent gastric cancer treated with radiotherapy (RT) using modern 3-dimensional conformal techniques. We retrospectively reviewed patients who had palliative RT for index symptoms of gastric bleeding, pain, and obstruction. Study endpoints included symptom response, median survival, and treatment toxicity. Of 115 patients with median age of 77 years, 78 (67.8%) patients had metastatic disease at the time of treatment. Index symptoms were gastric bleeding, pain, and obstruction in 89.6%, 9.2%, and 14.3% of patients, respectively. Dose fractionation regimen ranged from 8-Gy single fraction to 40 Gy in 16 fractions. One hundred eleven patients (93.3%) were computed tomography (CT) planned. Median follow-up was 85 days. Response rates for bleeding, pain, and obstruction were 80.6% (83/103), 45.5% (5/11), and 52.9% (9/ 17), respectively, and median duration of response was 99 days, 23 days, and 97 days, respectively. Median survival was 85 days. Actuarial 12-month survival was 15.3%. There was no difference in response rates between low (≥39 Gy) and high (>39 Gy) biologically effective dose (BED) regimens (α/β ratio=10). Median survival was significantly longer in patients who responded to RT compared with patients who did not (113.5 vs 47 days, P<0.001). Three patients (2.6%) had grade 3 Common Toxicity Criteria equivalent toxicity (nausea/vomiting/anorexia). External beam RT delivered using 3-dimensional conformal techniques is highly effective and well tolerated in the local palliation of gastric cancer, with palliation lasting the majority of patient's lives. Short (≤39 Gy BED) RT schedules are adequate for effective symptom palliation. A phase II study of palliative gastric RT is ongoing. Copyright © 2014 Wolters Kluwer Health-Lippincott Williams & Wilkins. Source