Novel Synthetic Histone Deacetylase Inhibitor, SK-7041, Has Potent Anti-Proliferative Activity in Acute Myeloid Leukemia Cell Lines.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2854-2854
Author(s):  
Sung-Soo Yoon ◽  
Eunkyung Bae ◽  
Juwon Park ◽  
Yongjun Cha ◽  
Young Y. Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Histone Deacetylase Inhibitors ◽  
Expression Profiles ◽  
Leukemia Cell ◽  
Gene Expression Profiles ◽  
Myelogenous Leukemia ◽  
G1 Arrest ◽  
Cancer Cell Growth

Abstract Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities determine the acetylation status of histones, which regulates gene expression through chromatin remodeling. Aberrant histone acetylation is known to play a key role in leukemogenesis. Thus, histone deacetylase inhibitors (HDACIs) are emerging as a new class of anti-cancer agents for leukemia. In this study, we examined anti-proliferative effects of novel hybrid synthetic HDACI, SK-7041, in various acute myelogenous leukemia (AML) cell lines (KG-1, HL-60, HEL, U937, ML-1). SK-7041 induced the time-dependent hyperacetylation of histones H3 and H4 in AML cell lines. It preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, as compared with the other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041. All the cell lines tested showed similar patterns of growth inhibition by SK-7041. Their IC50 values were approximately 0.5 mM at 72 hours incubation. SK-7041 effectively induced the apoptosis via activation of caspase-3, -7, -9, and PARP, but not caspase-8. SK-7041 enhanced G1 arrest via decreasing Cyclin D1 expression and increasing p21 expression. Changes in gene expression profiles after treating KG-1 cells with various concentrations of SK-7041 were assessed using a cDNA microarray consisting of distinct cDNAs of cancer-related genes. 7 genes, namely RGL1, FYN, CARD9, ABCA7, TNFRSF6B, CASP9, and ENPP2 were induced substantially (Global M >2.0) and 8 genes, namely PTPN7, CD34, INSIG1, IL16, LHX6, TRIB3, BID, and PDCD4 were reduced substantially (Global M < 2.0). In conclusion, this study showed SK-7041 inhibited cancer cell growth and caused characteristic gene expression profile changes in AML cells. The alteration in levels of acetylated histones was closely associated with expression of specific cancer-related genes in AML cells.

PI3K/AKT/mTOR Signaling Is a Significant Druggable Pathway In Infant Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1669-1669 ◽  
Author(s):  
Karen A. Urtishak ◽  
Wang Li-San ◽  
David T. Teachey ◽  
Tasian K. Sarah ◽  
Jeffrey S. Barrett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cell Lines ◽  
Expression Profiles ◽  
Leukemia Cell ◽  
Gene Expression Profiles ◽  
Cell Killing ◽  
Mtor Signaling ◽  
Cell Death Pathway ◽  
Mtt Assays

Abstract Introduction Infant acute lymphoblastic leukemia (ALL) is an orphan disease with unmet need for safe effective therapies. This is an urgent problem because conventional chemotherapies are ineffective and have life-threatening toxicities in infants. Although the MLL rearrangements occurring in 75% of cases are associated with poor outcome, survival is inferior whether MLL is rearranged or not. We recently reported that infant ALL proved sensitive to obatoclax mesylate (GeminX Pharmaceuticals; now an indirect, wholly owned subsidiary of Teva Pharmaceutical Industries Ltd.) in vitro regardless of poor prognostic features including MLL gene rearrangement. Moreover, we showed that the leukemia cell killing by obatoclax involved apoptosis, necroptosis and autophagy (Urtishak et al., Blood 2013). Therefore, the recent pharmaceutical abandonment of obatoclax led us to search for similarly acting drugs, the Results of which identified the well-known antipsychotic thioridazine as a candidate for potential repurposing. Methods Correlative analyses were performed between basal gene expression profiles at leukemia diagnosis and single agent obatoclax EC50 values from MTT assays in 47 cases of infant ALL from the Children's Oncology Group P9407 trial (25 MLL-AF4; 8 MLL-ENL; 7 other MLL-rearranged; 7 MLL-germline) in order to find a priori determinants of obatoclax sensitivity; significant genes were further studied by Ingenuity Pathway Analysis (IPA). A search for similarly acting compounds was conducted by Connectivity Map analysis of gene expression profiles of MLL-AF4 ALL cell lines after obatoclax treatment. MTT assays without and with cell death pathway inhibition, Western blot and flow cytometric cell death assays, and phosphoflow cytometric signaling analyses were utilized to investigate activity and target modulation by potential candidates. Results IPA identified significant correlations between basal gene expression of the mTOR and downstream intersecting eIF4/p70S6K signaling programs and obatoclax EC50 in all 47 primary cases of infant ALL, as well as in the subset of the 25 cases with MLL-AF4 rearrangements. Consistent with the relevance of this pathway in leukemia cell killing that was suggested by the basal gene expression profiles in the primary cases, the Connectivity Map analysis of obatoclax-treated cell lines for compound matching returned a number of highly ranked PI3K/AKT/mTOR signal transduction inhibitors as potential obatoclax substitutes. Three of the compounds (LY294002, wortmannin, thioridazine) were not only cytotoxic in MLL-AF4 ALL cell lines, but also they abrogated PI3K/AKT/mTOR signaling as indicated by robust inhibition of phosphorylated S6. Of these compounds, the phenothiazine derivative thioridazine, which has been used clinically for decades as a neuroleptic, was of high interest because of potential advantages of drug repurposing for more rapid drug advancement. Moreover, detailed flow cytometric and Western blot analyses, and MTT assays of thioridazine in the presence of cell death pathway inhibitors validated activation of all three cell death mechanisms in the MLL-AF4 ALL cell lines similarly to obatoclax. Conclusions Thioridazine is a well-known antipsychotic drug that also has recently recognized properties as a PI3K/AKT/mTOR signaling inhibitor and as an inhibitor of other pathways relevant to cancer. In MLL-AF4 ALL cell lines characterized by the most common chromosomal translocation in infant ALL, single-agent thioridazine is highly cytotoxic, robustly inhibits PI3K/AKT/mTOR signaling and, moreover, like obatoclax, demonstrates activity as a multi-cell-death pathway agonist. Further preclinical studies now are warranted to determine the extent to which thioridazine inhibits PI3K/AKT/mTOR signaling and causes leukemia cell killing in primary infant ALL cells in vitro and in vivo. The repurposing strategy that this drug may allow could have promise to streamline drug development in infant ALL where the need for new therapies is so urgent. Disclosures: No relevant conflicts of interest to declare.

A Multi-Center and Multi-National Program To Assess the Clinical Accuracy of the Molecular Subclassification of Leukemia by Gene Expression Profiling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 757-757 ◽  
Author(s):  
Torsten Haferlach ◽  
Alexander Kohlmann ◽  
Guiseppe Basso ◽  
Marie-Christine Bene ◽  
James R. Downing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Research Study ◽  
Expression Profiles ◽  
Blast Crisis ◽  
Leukemia Cell ◽  
Gene Expression Profiles ◽  
Chronic Phase ◽  
High Reproducibility ◽  
Clinical Accuracy

Abstract Microarray analysis can identify differentially expressed genes associated with distinct clinical and therapeutically relevant classes of both pediatric and adult leukemias. Recently, the MILE (Microarray Innovations in Leukemia) research study program has been launched in 10 centers: 7 from the European Leukemia Network (ELN, WP13) and 3 from the US. In this study, which will include 4,000 patients, the clinical accuracy of gene expression profiles of 16 acute and chronic leukemia subclasses, MDS, and non-leukemia as control will be assessed as compared to current routine diagnostic workup. Each center is trained on an identical microarray protocol and uses the same laboratory equipment, kits, and reagents for target preparation (Affymetrix HG-U133 Plus 2.0). First, the intra- and inter-laboratory comparability was investigated using 2 different cell line samples, MCF-7 and HEPG2, with different amounts of starting material (1 μg and 5 μg input for cDNA synthesis). Also, each center prepared in parallel total RNA and processed replicate samples from three leukemia pts (AML with t(8;21), CML, and CLL). We found a high reproducibility among the different centers: unsupervised analyses accordingly group the two different cell lines distinct from the three types of leukemia samples. In hierarchical clustering and principal component analysis the non-leukemia samples are clearly distinct from the leukemia samples and no clustering of the individual centers can be seen. Remarkably, for the replicates of the leukemia samples the squared correlation coefficients of gene expression range between 0.975 and 0.997 for CML, between 0.975 and 0.998 for CLL, and between 0.970 and 0.999 for the AML with t(8;21). Secondly, the samples were analyzed by a classification algorithm. The algorithm was trained on a database that contains gene expression profiles of &gt;1,600 leukemia patients and cell lines and can distinguish 16 different classes of leukemia, MDS, and non-leukemia. Several methods are used to form linear classifiers for all 18 * (18 – 1)/2 = 153 class pairs. The average cross-validation accuracy is 91% or higher. Miscalls are predominantly seen in the distinction between MDS and AML with normal karyotype. The accuracy of resubstitution (application of the classifier to the data forming the classifier) is 100%. For the new data accurate predictions for the non-leukemia cell lines, AML with t(8;21), and CLL were observed. Interestingly, the CML in blast crisis is predicted as AML with other abnormalities. This may be due to the fact that the classifier was trained on CML in chronic phase only. In conclusion, for the first time an international multi-center research study demonstrates a very high reproducibility of microarray analyses performed at different centers for the same leukemia samples. This lays the foundation for an international clinical research initiative evaluating the application of microarrays in the diagnosis and classification of hematological malignancies.

scholarly journals Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines

Oncogene ◽  
2002 ◽  
Vol 21 (42) ◽  
pp. 6549-6556 ◽  
Author(s):  
Jiafu Ji ◽  
Xin Chen ◽  
Suet Yi Leung ◽  
Jen-Tsan A Chi ◽  
Kent Man Chu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Gastric Cancer Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Comprehensive Analysis ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cell Lines

scholarly journals Changes in IDH2, TET2 and KDM2B Gene Expression After Treatment With Classic Chemotherapeutic Agents and Decitabine in Myelogenous Leukemia Cell Lines

2019 ◽  
Vol 8 (3) ◽  
pp. 89-101
Author(s):  
Jayse Alves ◽  
Georgia Muccillo Dexheimer ◽  
Laura Reckzigel ◽  
Marcia Goettert ◽  
Vanderlei Biolchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Leukemia Cell ◽  
Chemotherapeutic Agents ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Lines

Trichostatin A sensitivity signature across hematological cell lines.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19521-e19521
Author(s):  
Bartlomiej Przychodzen
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
B Lymphocyte ◽  
Trichostatin A ◽  
Expression Profiles ◽  
Cell Maturation ◽  
B Cell Maturation

e19521 Background: Histone deacetylase inhibitors (HDACi) are small molecules that increase acetylation of lysine residues by blocking histone deactylases. These anticancer agents affect epigenetic and non-epigenetic gene expression resulting in cell cycle arrest of cancer cells. Furthermore HDACi can enhance its anti-tumor effects via the pharmacologic modulation of macrophage. Some HDACi’s such as Trichostatin A (TSA) can also affected the tumor immune microenvironment by suppressing the activity of infiltrating macrophages and inhibiting myeloid-derived suppressor cell recruiement (Li et al.,). Methods: We conducted a high throughput screen comparing gene expression profiles in known hematological cell lines to identify transcriptional signatures associated with TSA sensitivity obtained from GDSC. Results: We selected genes that showed at least 2fold expression difference and were statistically significant (p < 0.05). We identified 49 genes that were upregulated and 85 that were downregulated. The most significant results include multiple genes known to be correlated with the B-cell maturation process. We found that CD24 a small GPI linked glycoprotein expressed at the surface of most B lymphocyte precursors, neutrophils, epithelial cells and frequently found to be highly expressed in various hematological and solid neoplasms, was up/downregulatred by XX. Interestingly, CD24 plays a role in the activation and differentiation of the cells as bone marrow samples lacking CD24 resulted in decreased numbers of both pre-B and immature B-cell populations. We also found that IKZF2, a transcription factor regulating lymphocyte development and queiesence and which is frequently deleted in hypodiploid B-ALLs. This result could revelent as other reports suggest a role of IKZF2 as a tumor suppressor with a central role regulating the balance of self-renewal and differentiation in leukemic stem cells. Conclusions: Our study identified transcriptional profiles which suggest that TSA sensitivity could be related to B cell maturation. Further experiments warrant replication of these findings which could prove useful in creating optimal, TSA-based treatments acting either as potent single agents or in combination enhancing anti-tumor effects of immunotherapies.

P4-124: Comparison of gene expression profiles of prion protein-deficient and wild type neuronal cell lines of mice

2006 ◽  
Vol 2 ◽  
pp. S552-S552
Author(s):  
Boe-Hyun Kim ◽  
Jae-Il Kim ◽  
Eun-Kyoung Choi ◽  
Richard I. Carp ◽  
Yong-Sun Kim
Keyword(s):  
Gene Expression ◽  
Prion Protein ◽  
Cell Lines ◽  
Expression Profiles ◽  
Neuronal Cell ◽  
Gene Expression Profiles ◽  
Wild Type ◽  
Neuronal Cell Lines

scholarly journals cDNA expression array reveals heterogeneous gene expression profiles in three glioblastoma cell lines

Oncogene ◽  
1999 ◽  
Vol 18 (17) ◽  
pp. 2711-2717 ◽  
Author(s):  
Chang Hun Rhee ◽  
Kenneth Hess ◽  
James Jabbur ◽  
Maribelis Ruiz ◽  
Yu Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Glioblastoma Cell ◽  
Expression Array ◽  
Cdna Expression Array ◽  
Cdna Expression ◽  
Glioblastoma Cell Lines
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