scholarly journals Carnosol induces apoptotic cell death through ROS-dependent inactivation of STAT3 in human melanoma G361 cells

2019 ◽  
Vol 62 (1) ◽  
Author(s):  
Seung Mi Choi ◽  
Do-Hee Kim ◽  
Kyung-Soo Chun ◽  
Joon-Seok Choi
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Human Melanoma ◽  
Dependent Manner ◽  
Bax Protein ◽  
Wide Range ◽  
Anti Cancer ◽  
Induced Apoptosis

Abstract Melanoma is the leading cause of skin cancer deaths, and the poor prognosis of metastatic melanoma has made needs for a novel pharmacological treatment or efficient intervention. Carnosol, a major polyphenolic compound from Rosmarinus officinalis, has a wide range of biological activities including anti-cancer effect. However, the underlying molecular mechanisms of its anti-cancer effect remain poorly understood in malignant human melanoma cells. In the present study, we investigate the apoptotic effect and the underlying anti-cancer mechanisms of carnosol. Our results revealed that carnosol strongly induced apoptosis against human melanoma G361 cells in a dose- and time-dependent manner, and caused dramatical elevation in cellular reactive oxygen species (ROS) level during apoptosis. In mechanistic studies, carnosol treatment decreased protein level of anti-apoptotic B‑cell lymphoma 2 (Bcl-2) and B cell lymphoma-extra large (Bcl-xL), however, increased level of pro-apoptotic Bcl-2-associated X protein (Bax) protein. Moreover, carnosol escalated cellular level of p53, which was accompanied by a decline of mouse double minute 2 homolog (MDM2) level. Also, carnosol inhibited activation of Src and signal transducer and activator of transcription 3 (STAT3), therefore down-regulated STAT3-dependent gene expression, such as D-series cyclin and survivin. These changes by carnosol were attenuated by pre-treatment of N-acetyl cysteine, and abolished progression of carnosol-induced apoptosis. In conclusion, carnosol induced apoptosis in human melanoma G361 cells through ROS generation and inhibition of STAT3-mediated pathway. Our results provide molecular bases of carnosol-induced apoptosis, and suggest a novel candidate for human melanoma treatment.

Rituximab Activation of AKT and HIF Pathways Is Dependent on Membrane Lipid Raft Cholesterol Levels in Lymphoma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1571-1571
Author(s):  
Yumi Nozaki ◽  
Toru Mitsumori ◽  
Norio Komatsu ◽  
Keita Kirito
Keyword(s):  
B Cell ◽  
Lipid Raft ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Membrane Cholesterol ◽  
Dependent Manner ◽  
Lymphoma Cells ◽  
Akt Activation ◽  
Cholesterol Levels ◽  
Induced Apoptosis

Abstract Abstract 1571 Rituximab, which is a monoclonal antibody directed against CD20 proteins, has significantly improved the treatment outcome of B-cell lymphoma patients. Recent studies have revealed that the lipid components of the membrane microdomain, also known as the lipid raft, determine the biological function and efficiency of the antibody. The raft-associated sphingolipid GM1 level also affects the susceptibility of lymphoma cells to rituximab. Clinical observations have suggested that the use of statins may affect the efficiency of rituximab by modulating lipid raft cholesterol levels. In the present study, we investigated whether differences in lipid raft components affected rituximab-induced intracellular signaling pathways and the biological activity of the antibody. Initially, we analyzed the membrane cholesterol and GM1 levels in several B-cell lymphoma cells (Raji, RL,Namalwa and Ramos cells). We found that two cell lines (Raji and RL cells) have higher cholesterol levels compared with Namalwa and Ramos cells; however, Namalwa and Ramos cells have higher GM1 expression compared with Raji and RL cells. Interestingly, rituximab clearly activated the PI3K/AKT pathway in the cholesterol-rich cells (Raji and RL cells). Conversely, treatment with rituximab suppressed the basal activity of AKT in the GM1-rich cells (Namalwa and Ramos cells). We also investigated whether cholesterol levels or the GM1 level affected rituximab-induced PI3K/AKT activation. We treated the cholesterol-rich cells with methyl-β-cyclodextrin (MβCD) to deplete cholesterol from the lipid rafts. Treatment with MβCD clearly disrupted rituximab-induced AKT activation. Importantly, cholesterol replacement restored rituximab-induced AKT activation. In contrast, treatment with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibits the synthesis of GM1, did not reverse rituximab-induced AKT suppression in the GM1-rich cells. These results suggest that lipid raft cholesterol levels, but not the GM1 level, determine rituximab-induced AKT activation. We also examined the biological significance of rituximab-induced AKT activation in lymphoma cells. Although AKT activates a variety of downstream molecules, we focused our attention on hypoxia-inducible factor (HIF) because recent studies have revealed that abnormal expression of the alpha subunit of HIF-1 (HIF-1α) is frequently found in lymphoma cells. In agreement with the finding that rituximab induced AKT activation, treatment with rituximab markedly increased the expression of HIF-1α in the cholesterol-rich cells. In contrast, rituximab reduced the basal HIF-1α level in the GM1-rich cells. Interestingly, rituximab enhanced the expression of the anti-apoptotic protein survivin in a HIF-1-dependent manner in Raji and RL cells. In addition, rituximab suppressed the chemotherapeutic reagent-induced apoptosis of Raji and RL cells. Interestingly, depletion of membrane cholesterol by MβCD completely blocked all these processes. In conclusion, rituximab exerts different effects on lymphoma cells that are dependent on lipid raft cholesterol levels. Our observations suggest that a high level of membrane cholesterol may diminish rituximab-induced apoptosis through AKT activation and subsequent induction of HIF-1α. Importantly, a reduction of membrane cholesterol may enhance the efficiency of rituximab. Disclosures: No relevant conflicts of interest to declare.

ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1454-1463 ◽  
Author(s):  
Nathalie Chevallier ◽  
Connie M. Corcoran ◽  
Christine Lennon ◽  
Elizabeth Hyjek ◽  
Amy Chadburn ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Lymphoma ◽  
Common Factor ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Dependent Manner ◽  
B Cell Lymphomas ◽  
Acute Leukemias

Abstract The multiplicity of transcription factors involved in hematologic malignancies suggests a complicated scenario in which many different molecular mechanisms lead to malignant transformation. We hypothesized that some of these proteins might physically and functionally interact and thus mechanistically link different diseases. The ETO protein of t(8;21) acute myeloid leukemia (AML) is an excellent candidate as a common factor because it is normally expressed in human hematopoietic cells, it binds to histone deacetylases (HDACs), and it interacts with the PLZF protein of t(11;17) acute promyelocytic leukemia. To determine whether ETO functionally links a broader range of disease entities, we asked whether ETO forms a complex with the Bcl-6 oncoprotein of B-cell lymphomas. We found that ETO and Bcl-6 are coexpressed in normal and malignant lymphoid tissue, where they interact and colocalize in nuclear speckles. ETO binds to the fourth zinc finger of Bcl-6, enhances Bcl-6 repression of artificial and endogenous genes in an HDAC-dependent manner, and forms a complex with Bcl-6 on the promoters of its endogenous target genes in B-cell lymphoma cells. Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies.

TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas

Blood ◽  
2009 ◽  
Vol 114 (12) ◽  
pp. 2467-2475 ◽  
Author(s):  
Keiichiro Honma ◽  
Shinobu Tsuzuki ◽  
Masao Nakagawa ◽  
Hiroyuki Tagawa ◽  
Shigeo Nakamura ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Suppressor Gene ◽  
Negative Regulator ◽  
Barr Virus ◽  
Induced Apoptosis

AbstractThe constitutive activation of nuclear factor-κB (NF-κB) has been implicated in tumorigenesis of lymphoid malignancies. We have previously shown that chromosome 6q was frequently deleted in ocular marginal zone B-cell lymphoma and identified TNFAIP3/A20, a negative regulator of NF-κB pathways, as the primary target for 6q deletion. In the study reported here, we extended the analysis to other subsets of non-Hodgkin lymphomas and found that A20 is frequently deleted in mantle cell lymphoma and diffuse large B-cell lymphoma. Importantly, A20 promoter methylation or gene mutation is also frequently detected in these lymphomas, raising the possibility that inactivation of A20 may be involved in lymphomagenesis. To address this question, we conducted overexpression experiments in lymphoma cell lines with A20 deletion and down-regulated expression of A20 with an siRNA technique in Epstein-Barr virus–infected lymphoblastoid cell lines. These experiments found that overexpression of A20 induced apoptosis and silencing of A20 was associated with resistance to apoptosis and enhanced clonogenicity. The cells with down-regulated A20 exhibited enhanced NF-κB activities, which may account for the observed effects. These results indicate that our study provides a novel insight into molecular mechanisms leading to lymphoma and that specific targeting of NF-κB pathways may be advantageous for treatment.

scholarly journals Regulation of HACE1 Expression Enhances HDAC Inhibitor Lmk-235-Mediated Apoptosis in Diffuse Large B-Cell Lymphoma Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5299-5299
Author(s):  
Xinyao Li ◽  
Dan Ma ◽  
Tingting Lu ◽  
Xingyi Kuang ◽  
Kunling Yu ◽  
...  
Keyword(s):  
B Cell ◽  
Hdac Inhibitor ◽  
Cell Lymphoma ◽  
Epigenetic Modification ◽  
Treatment Plan ◽  
B Cell Lymphoma ◽  
Dependent Manner ◽  
Large B Cell Lymphoma ◽  
Induced Apoptosis ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma (NHL). It is a group of adult lymphomas with a large clinical presentation and prognosis heterogeneity. In order to improve the cure rate of diffuse large B-cell lymphoma, it is necessary to find a new DLBCL treatment plan that can control the progression of the disease and explore its unknown potential therapeutic targets. Epigenetic modification has become a new treatment for leukemia in recent years, and histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL in recent years. However, in addition to effective clinical efficacy, Pan-HDACis has side effects. In contrast, LMK-235 is well tolerated as a novel inhibitor of HDAC4 and HDAC5. HACE1 is a potential tumor suppressor gene located on chromosome 6q21, which is involved in the regulation of tumor cell growth and apoptosis by mediating autophagy and ubiquitination of Rac1. The potential target of HACE1 as an HDAC inhibitor plays an important role in the occurrence, invasion and metastasis of human malignant tumors, but its underlying mechanism of HDACi-mediated apoptosis is still unclear. In this study, we investigated the potential mechanisms by which HACE1 regulates LMK-235-mediated apoptosis in DLBCL cells. In vitro, LMK-235 mediates apoptosis in DLBCL cells in a dose-dependent manner, and up-regulation of HACE1 by lentiviral transfection promotes LMK-235-induced apoptosis. At the same time, high levels of HACE1 can inhibit the expression of HO-1 at mRNA and protein levels. As a previous study in our laboratory, low expression of HO-1 enhanced the apoptotic rate of DLBCL cells. However, the correlation between HACE1 and HO-1 has not been reported. Therefore, we regulated HACE1 levels and found that HACE1 regulates HO-1, which affects the sensitivity of DLBCL cells to LMK-235. Our data show that HACE1 plays a key role in LMK-235-induced apoptosis in DLBCL cells. This provides new hope for the treatment of diffuse large B-cell lymphoma and is a potential new target for the treatment of diffuse large B-cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Mechanism of Acadesine-Induced Apoptosis in B-Cell Neoplasms.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4822-4822
Author(s):  
Antonio F. Santidrián ◽  
Clara Campàs ◽  
Llorenç Coll-Mulet ◽  
Daniel Iglesias-Serret ◽  
Ana M. Cosialls ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Adenosine Monophosphate ◽  
Lymphocytic Leukemia ◽  
Regulatory Subunit ◽  
Akt Phosphorylation ◽  
Bax Protein ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Mature B-cell neoplasms include B-cell chronic lymphocytic leukemia (B-CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and splenic marginal zone B-cell lymphoma (SMZL), among others. We found that acadesine, 5-aminoimidazole-4-carboxamide (AICA) riboside, induced apoptosis in B-cell neoplasms and in normal B lymphocytes, but FL samples were resistant. T cells from these patients or from healthy donors were not affected (Campas et al. Blood101: 3674, 2003; Campas et al. Leukemia19: 292, 2005). We have studied the mechanism of acadesine-induced apoptosis. Acadesine uptake and phosphorylation to ZMP are necessary to induce apoptosis. The best known molecular target of ZMP described to date is adenosine monophosphate-activated protein kinase (AMPK). We have analyzed the expression of LKB1, an AMPKK, AMPK isoforms and related proteins in B-CLL cells. B-CLL cells express LKB1, the α1 catalytic isoform of AMPK and both the β1 and β2 isoforms of the β regulatory subunit, but do not express the α2 isoform. Moreover, the AMPK related protein Snark is expressed in B-CLL cells, while Melk and Ark5 are not. Incubation of B-CLL, MCL, SMZL cells with acadesine induces phosphorylation in Thr172 and activation of AMPK, which correlates with induction of apoptosis. Acadesine enters FL cells as it induces phosphorylation of AMPK, however FL cells are resistant to acadesine-induced apoptosis. Moreover, phenformin and metformin induce AMPK phosphorylation but not induce apoptosis in B-CLL cells. The phosphorylation of AMPK is not sufficient for induction of apoptosis by acadesine in B-cell neoplasms. In B-CLL cells, CD40L or TPA, but not IL-4 or SDF1 inhibit acadesine-induced apoptosis. Acadesine inhibit neither AKT phosphorylation induced by TPA, IL-4, SDF1 or CD40L nor basal AKT phosphorylation. Finally, acadesine induces a conformational change in Bax protein, and citochrome c release to cytosol which is not block by ZVAD.fmk. In conclusion, although further studies are necessary to elucidate the mechanism of acadesine-induced apoptosis, we propose that acadesine may provide an effective treatment for mature B-cell neoplasms such as B-CLL, MCL and SMZL.

Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma

1997 ◽  
Vol 25 (2) ◽  
pp. 705-708 ◽  
Author(s):  
D. R. Anderson ◽  
A. Grillo-López ◽  
C. Varns ◽  
K. S. Chambers ◽  
N. Hanna
Keyword(s):  
Cancer Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Anti Cancer ◽  
Cd20 Antibody ◽  
Anti Cd20

scholarly journals Anti-Cancer Effects of CKD-581, a Potent Histone Deacetylase Inhibitor against Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 21 (12) ◽  
pp. 4377
Author(s):  
Soo Jin Kim ◽  
U Ji Kim ◽  
Hae Yong Yoo ◽  
Yong June Choi ◽  
Keon Wook Kang
Keyword(s):  
B Cell ◽  
Histone Deacetylase ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mouse Xenograft Model ◽  
Anti Cancer ◽  
Large B Cell

Double-hit lymphoma (DHL) and double-expressor lymphoma (DEL) are aggressive forms of lymphoma that require better treatments to improve patient outcomes. CKD-581 is a new histone deacetylase (HDAC) inhibitor that exhibited a better safety profile in clinical trials compared to other HDAC inhibitors. Here, we demonstrate that CKD-581 inhibited the class I–II HDAC family via histone H3 and tubulin acetylation. CKD-581 treatment also up-regulated the phosphorylation of histone H2AX (γH2AX, DNA double-strand break marker), and reduced levels of MYC and anti-apoptotic proteins such as BCL-2, BCL-6, BCL-XL, and MCL-1 in DH/DE-diffuse large B cell lymphoma (DLBCL) cell lines. Ultimately, CKD-581 also induced apoptosis via poly(ADP ribose) polymerase 1 (PARP1) cleavage. In a DLBCL SCID mouse xenograft model, CKD-581 exhibited anti-cancer effects comparable with those of rituximab (CD20 mAb). Our findings suggest that CKD-581 could be a good candidate for the treatment of DLBCL.

‘Piperazining’ the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib

2019 ◽  
Vol 11 (18) ◽  
pp. 2365-2380
Author(s):  
Aimen K Aljoundi ◽  
Clement Agoni ◽  
Fisayo A Olotu ◽  
Mahmoud ES Soliman
Keyword(s):  
Molecular Dynamics ◽  
B Cell ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dynamics Simulation ◽  
Large B Cell Lymphoma ◽  
Dynamics Simulations ◽  
Large B Cell

Aim: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive. Materials & methods: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib. Results: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 – LYN; Asp130/Asp148/Glu54 – FYN; Asp89 – BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves. Conclusion: Identification of these ‘gatekeeper’ residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.

scholarly journals Hypoxia-Inducible Factor-1 α Expression Predicts Superior Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP

2010 ◽  
Vol 28 (6) ◽  
pp. 1017-1024 ◽  
Author(s):  
Andrew M. Evens ◽  
Laurie H. Sehn ◽  
Pedro Farinha ◽  
Beverly P. Nelson ◽  
Adekunle Raji ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Wide Range ◽  
Large B Cell

Purpose Hypoxia-inducible factor (HIF) controls the expression of genes in response to hypoxia, as well as a wide range of other cellular processes. We previously showed constitutive stabilization of HIF-1α in the majority of patients with diffuse large B-cell lymphoma (DLBCL). To our knowledge, the prognostic significance of HIF in lymphoma has never been investigated. Patients and Methods We studied the immunohistochemical protein expression of HIF-1α on tissue microarrays from 153 patients with DLBCL treated in sequential cohorts with cyclophosphamide, doxorubicin, oncovin, and prednisone (CHOP) or rituximab-CHOP (R-CHOP) from 1999 to 2002. Results were correlated with patient outcome. Results Median follow-up for all patients was 80 months. Among all patients, HIF-1α was expressed in 62% of germinal center and 59% of non–germinal center patients. With HIF-1α analyzed as a dependent variable, there were no survival differences in CHOP-treated patients. In the R-CHOP group, however, HIF-1α protein expression correlated with significantly improved progression-free survival (PFS) and overall survival (OS). Five-year PFS for HIF-1α–positive patients was 71% v 43% for HIF-1α–negative patients (P = .0187), whereas 5-year OS was 75% and 54%, respectively (P = .025). In multivariate analysis with International Prognostic Index criteria, HIF-1α remained a significant predictor for PFS (P = .026) and OS (P = .043). Compared with other biomarkers, HIF-1α correlated only with BCL6 (P = .004). In terms of gene expression, we found several common gene associations of HIF-1α and the stromal-1 signature with genes predominantly involved in regulation of the extracellular matrix (eg, BGN, COL1A2, COL5A1, and PLOD2). Conclusion The expression of HIF-1α protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP.

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