Inhibition von Mcl-1 (Myeloid-Cell Leukemia 1) und Bcl-2 (B-Cell Lymphoma 2) - Ein neuer Therapieansatz bei Hepatozellulärem Karzinom (HCC)

2021 ◽  
Author(s):  
M Bauer ◽  
M Michalski ◽  
C Kunst ◽  
M Müller-Schilling ◽  
K Gülow
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Leukemia

Differential expression of apoptosis-associated genes in canine mammary tumors

Biologia ◽  
2015 ◽  
Vol 70 (6) ◽  
Author(s):  
Namita Mitra ◽  
Ramneek Verma ◽  
Dipak Deka ◽  
Hitesh N. Pawar ◽  
Naresh K. Sood ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Mammary Tumors ◽  
Cell Leukemia ◽  
Pcr Assay ◽  
Canine Mammary Tumors ◽  
Poorly Differentiated ◽  
Maximum Expression

AbstractB-cell lymphoma 2 (Bcl-2) and heat shock protein (HSP) families are implicated in various processes of carcinogenesis, owing to their role in regulation of apoptosis and cell cycle, respectively. mRNA expression of Bcl-2, myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-extra-large (Bcl-xl), Bcl2-associated X (Bax), HSP70 and HSP90-β genes were studied in 30 clinical canine mammary tumors (CMTs). Histological ‘type’ and ‘grade’ were assigned to CMTs and expression was evaluated by SYBR-Green real-time PCR assay. Overall, the tumors exhibited the maximum expression of Bcl-2 amongst the Bcl-2 family members. Sarcoma and carcinosarcoma showed relatively higher expression of Mcl-1, whereas Bcl-2 was over-expressed in carcinoma. In relation to the cancer grades, Bcl-2/Bax ratio tend to increase as the tumor differentiation progressed from well to poorly differentiated. HSP90-β exhibited significantly high expression in carcinoma, carcinosarcoma and all grades of CMTs were suggestive of their elemental role in tumor progression. In conclusion, this study underpins the conjecture that Bcl-2, Mcl-1 and HSP90-β can be used as potential targets of inhibition in future mammary tumor therapeutics.

Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1

2011 ◽  
Vol 83 (3) ◽  
pp. 723-731 ◽  
Author(s):  
Paul H. Bernardo ◽  
Thirunavukkarasu Sivaraman ◽  
Kah-Fei Wan ◽  
Jin Xu ◽  
Janarthanan Krishnamoorthy ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Binding Modes ◽  
Cell Leukemia ◽  
Compound Library

A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu-Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.

scholarly journals Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL

Blood ◽  
2019 ◽  
Vol 133 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Xenograft Model ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Synergistic Activity ◽  
Genetic Bases

Abstract Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.

scholarly journals BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 938 ◽  
Author(s):  
Magdalena Klanova ◽  
Pavel Klener
Keyword(s):  
B Cell ◽  
Protein Interactions ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Apoptosis ◽  
Clinical Testing ◽  
Cell Leukemia ◽  
The Status ◽  
B Cell Leukemia

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

Epstein-Barr virus (EBV) genome carrying monoclonal B-cell lymphoma in a patient with adult T-cell leukemia-lymphoma

1991 ◽  
Vol 15 (9) ◽  
pp. 837-846 ◽  
Author(s):  
Kensei Tobinai ◽  
Tomoko Ohtsu ◽  
Masaki Hayashi ◽  
Tomohiro Kinoshita ◽  
Yoshihiro Matsuno ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Barr Virus ◽  
Epstein Barr
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