scholarly journals Application and research progress of BCL2 inhibitors in elderly patients with hematologic malignancies

2020 ◽  
Vol 2 (4) ◽  
pp. 180-186
Author(s):  
Yufan Wang ◽  
◽  
Liang Wang ◽  
Keyword(s):  
Elderly Patients ◽  
Cancer Cells ◽  
Hematological Malignancies ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Research Progress ◽  
Antiapoptotic Proteins ◽  
Bcl2 Family ◽  
Apoptotic Protein

Apoptosis is a process of programmed cell death which mediated by proteases called caspases. Deregulated apoptosis is the basis of a variety of diseases, including cancer. The pathways of apoptosis can be divided into two independent signaling pathways, intrinsic or extrinsic. B-cell lymphoma 2 family proteins including BCL2 anti-apoptotic protein play an important role in the regulation of caspases in intrinsic pathways. Since that BCL2 is often overexpressed in cancer cells, a series of inhibitors targeting the BCL2 family antiapoptotic proteins have been developed to induce apoptosis in cancer cells. The highly selective BCL2 inhibitors, such as venetoclax (ABT-199, Venclexta™) and navitoclax(ABT-263), have shown good efficacy and safety in many hematologic malignancies. Considering that elderly patients with hematological malignancies still lack effective treatments, BCL2 inhibitors are undoubtedly an attractive new therapy due to their desirable safety and efficacy. This article reviews the application and research progress of BCL2 inhibitors in elderly patients with hematologic malignancies. Keywords: BCL2 inhibitors, hematologic malignancies, venetoclax, elderly patients

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

2020 ◽  
Author(s):  
Melissa A. Fischer ◽  
Yuanbin Song ◽  
Rana Gbyli ◽  
Maria P. Arrate ◽  
Matthew T. Villaume ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Bcl2 Family ◽  
Apoptotic Protein ◽  
Clinical Complexity ◽  
Therapeutic Opportunity ◽  
Dual Inhibition

AbstractTreatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and clinical complexity. Dysregulation of apoptosis is observed across MDS subtypes regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma-2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML). BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. Here, we determined the in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with increasing blast counts, all MDS subtypes responded to the MCL1 inhibitor, S63845. Treatment with combined VEN+S63845 was synergistic in all MDS subtypes and reduced MDS engraftment in MISTRG6 mice supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

Anticancer Activity of Platinum (II) Complex with 2-Benzoylpyridine by Induction of DNA Damage, S-Phase Arrest, and Apoptosis

2020 ◽  
Vol 20 (4) ◽  
pp. 504-517
Author(s):  
Yu-Lan Li ◽  
Xin-Li Gan ◽  
Rong-Ping Zhu ◽  
Xuehong Wang ◽  
Duan-Fang Liao ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cell ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
S Phase ◽  
Caspase 9

Objective: To overcome the disadvantages of cisplatin, numerous platinum (Pt) complexes have been prepared. However, the anticancer activity and mechanism of Pt(II) complexed with 2-benzoylpyridine [Pt(II)- Bpy]: [PtCl2(DMSO)L] (DMSO = dimethyl sulfoxide, L = 2-benzoylpyridine) in cancer cells remain unknown. Methods: Pt(II)-Bpy was synthesized and characterized by spectrum analysis. Its anticancer activity and underlying mechanisms were demonstrated at the cellular, molecular, and in vivo levels. Results: Pt(II)-Bpy inhibited tumor cell growth, especially HepG2 human liver cancer cells, with a halfmaximal inhibitory concentration of 9.8±0.5μM, but with low toxicity in HL-7702 normal liver cells. Pt(II)- Bpy induced DNA damage, which was demonstrated through a marked increase in the expression of cleavedpoly (ADP ribose) polymerase (PARP) and gamma-H2A histone family member X and a decrease in PARP expression. The interaction of Pt(II)-Bpy with DNA at the molecular level was most likely through an intercalation mechanism, which might be evidence of DNA damage. Pt(II)-Bpy initiated cell cycle arrest at the S phase in HepG2 cells. It also caused severe loss of the mitochondrial membrane potential; a decrease in the expression of caspase-9 and caspase-3; an increase in reactive oxygen species levels; the release of cytochrome c and apoptotic protease activation factor; and the activation of caspase-9 and caspase-3 in HepG2 cells, which in turn resulted in apoptosis. Meanwhile, changes in p53 and related proteins were observed including the upregulation of p53, the phosphorylation of p53, p21, B-cell lymphoma-2-associated X protein, and NOXA; and the downregulation of B-cell lymphoma 2. Moreover, Pt(II)-Bpy displayed marked inhibitory effects on tumor growth in the HepG2 nude mouse model. Conclusion: Pt(II)-Bpy is a potential candidate for cancer chemotherapy.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

Reduced-dose ICE chemotherapy ± rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma

2015 ◽  
Vol 57 (7) ◽  
pp. 1633-1639 ◽  
Author(s):  
Nadav Sarid ◽  
Erel Joffe ◽  
Lili Gibstein ◽  
Irit Avivi ◽  
Aaron Polliack ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Salvage Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Reduced Dose ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Serum Levels of B-cell Lymphoma-2 Anti-Apoptotic Protein and Malignant Middle Cerebral Artery Infarction Mortality

2021 ◽  
Vol 30 (5) ◽  
pp. 105717
Author(s):  
Leonardo Lorente ◽  
María M. Martín ◽  
Agustín F. González-Rivero ◽  
Antonia Pérez-Cejas ◽  
Luis Ramos-Gómez ◽  
...  
Keyword(s):  
B Cell ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Serum Levels ◽  
Middle Cerebral Artery Infarction ◽  
Apoptotic Protein
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