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Dirk P Dittmer - One of the best experts on this subject based on the ideXlab platform.
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interleukin 1 receptor associated kinase irak signaling in kaposi sarcoma associated herpesvirus induced Primary Effusion Lymphoma
Journal of Virology, 2020Co-Authors: Jedediah Seltzer, Razia Moorad, Jason M Schifano, Justin T Landis, Dirk P DittmerAbstract:Kaposi sarcoma-associated herpesvirus (KSHV) is necessary but not sufficient for Primary Effusion Lymphoma (PEL) development. Alterations in cellular signaling pathways are also a characteristic of PEL. Other B cell Lymphomas have acquired an oncogenic mutation in the myeloid differentiation Primary response 88 (MYD88) gene. The MYD88 L265P mutant results in the activation of interleukin-1 receptor associated kinase (IRAK). To probe IRAK/MYD88 signaling in PEL, we employed CRISPR/Cas9 technology to generate stable deletion clones in BCBL-1Cas9 and BC-1Cas9 cells. To look for off-target effects, we determined the complete exome of the BCBL-1Cas9 and BC-1Cas9 cells. Deletion of either MYD88, IRAK4, or IRAK1 abolished interleukin-1 beta (IL-1β) signaling; however, we were able to grow stable subclones from each population. Transcriptome sequencing (RNA-seq) analysis of IRAK4 knockout cell lines (IRAK4 KOs) showed that the IRAK pathway induced cellular signals constitutively, independent of IL-1β stimulation, which was abrogated by deletion of IRAK4. Transient complementation with IRAK1 increased NF-κB activity in MYD88 KO, IRAK1 KO, and IRAK4 KO cells even in the absence of IL-1β. IL-10, a hallmark of PEL, was dependent on the IRAK pathway, as IRAK4 KOs showed reduced IL-10 levels. We surmise that, unlike B cell receptor (BCR) signaling, MYD88/IRAK signaling is constitutively active in PEL, but that under cell culture conditions, PEL rapidly became independent of this pathway.IMPORTANCE One hundred percent of Primary Effusion Lymphoma (PEL) cases are associated with Kaposi sarcoma-associated herpesvirus (KSHV). PEL cell lines, such as BCBL-1, are the workhorse for understanding this human oncovirus and the host pathways that KSHV dysregulates. Understanding their function is important for developing new therapies as well as identifying high-risk patient groups. The myeloid differentiation Primary response 88 (MYD88)/interleukin-1 receptor associated kinase (IRAK) pathway, which has progrowth functions in other B cell Lymphomas, has not been fully explored in PEL. By performing CRISPR/Cas9 knockout (KO) studies targeting the IRAK pathway in PEL, we were able to determine that established PEL cell lines can circumvent the loss of IRAK1, IRAK4, and MYD88; however, the deletion clones are deficient in interleukin-10 (IL-10) production. Since IL-10 suppresses T cell function, this suggests that the IRAK pathway may serve a function in vivo and during early-stage development of PEL.
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targeting mtor with mln0128 overcomes rapamycin and chemoresistant Primary Effusion Lymphoma
Mbio, 2019Co-Authors: Carolina Carovegas, Aubrey Bailey, Rachele Bigi, Blossom Damania, Dirk P DittmerAbstract:ABSTRACT Primary Effusion Lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced Effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL. IMPORTANCE Primary Effusion Lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by Lymphomatous Effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.
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Targeting mTOR with MLN0128 Overcomes Rapamycin and Chemoresistant Primary Effusion Lymphoma
American Society for Microbiology, 2019Co-Authors: Carolina Caro-vegas, Aubrey Bailey, Rachele Bigi, Blossom Damania, Dirk P DittmerAbstract:Primary Effusion Lymphoma (PEL) is an aggressive and incurable malignancy, which is usually characterized by Lymphomatous Effusions in body cavities without tumor masses. PEL has no established treatment and a poor prognosis, with a median survival time shorter than 6 months. PEL usually develops in the context of immunosuppression, such as HIV infection or post-organ transplantation. The optimal treatment for PEL has not been established, as PEL is generally resistant to traditional chemotherapy. The molecular drivers for PEL are still unknown; however, PEL displays a constitutively active mammalian target of rapamycin (mTOR) pathway, which is critical for metabolic and cell survival mechanisms. Therefore, the evaluation of novel agents targeting the mTOR pathway could be clinically relevant for the treatment of PEL.Primary Effusion Lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL has a highly active mTOR pathway, which makes mTOR a potential therapeutic target. MLN0128 is an ATP-competitive inhibitor of mTOR that has entered clinical trials for solid tumors. Our results demonstrated that MLN0128 has a greater effect on inhibiting proliferation than the allosteric mTOR inhibitor rapamycin. MLN0128 has ∼30 nM 50% inhibitory concentration (IC50) across several PEL cell lines, including PEL that is resistant to conventional chemotherapy. MLN0128 induced apoptosis in PEL, whereas rapamycin induced G1 arrest, consistent with a different mechanism of action. MLN0128 inhibited phosphorylation of mTOR complex 1 and 2 targets, while rapamycin only partially inhibited mTOR complex 1 targets. PEL xenograft mouse models treated with MLN0128 showed reduced Effusion volumes in comparison to the vehicle-treated group. Rapamycin-resistant (RR) clones with an IC50 for rapamycin 10 times higher than the parental IC50 emerged consistently after rapamycin exposure as a result of transcriptional adaptation. MLN0128 was nevertheless capable of inducing apoptosis in these RR clones. Our results suggest that MLN0128 might offer a new approach to the treatment of chemotherapy-resistant PEL
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tumor suppressor genes fhit and wwox are deleted in Primary Effusion Lymphoma pel cell lines
Blood, 2011Co-Authors: Debasmita Roy, Blossom Damania, Sang Hoon Sin, Dirk P DittmerAbstract:Primary Effusion Lymphoma (PEL) is a diffuse-large B-cell Lymphoma with poor prognosis. One hundred percent of PELs carry the genome of Kaposi sarcoma-associated herpesvirus and a majority are coinfected with Epstein-Barr virus (EBV). We profiled genomic aberrations in PEL cells using the Affymetrix 6.0 SNP array. This identified for the first time individual genes that are altered in PEL cells. Eleven of 13 samples (85%) were deleted for the fragile site tumor suppressors WWOX and FHIT. Alterations were also observed in the DERL1, ETV1, RASA4, TPK1, TRIM56, and VPS41 genes, which are yet to be characterized for their roles in cancer. Coinfection with EBV was associated with significantly fewer gross genomic aberrations, and PEL could be segregated into EBV-positive and EBV-negative clusters on the basis of host chromosome alterations. This suggests a model in which both host genetic aberrations and the 2 viruses contribute to the PEL phenotype.
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tumor suppressor micrornas are underrepresented in Primary Effusion Lymphoma and kaposi sarcoma
Blood, 2009Co-Authors: Andrea J Ohara, Bruce J. Dezube, Blossom Damania, Ling Wang, William J Harrington, Dirk P DittmerAbstract:The presence of tumor-specific microRNAs reflects tissue of origin and tumor stage. We show that the absence of miRNAs likewise can be used to determine tumor origin (miR-155) and proliferation state because tumor suppressor miRNAs (miR-222/221, let-7 family) were significantly down-regulated in Primary Effusion Lymphoma (PEL) and in Kaposi sarcoma (KS), an endothelial cell tumor. PEL and KS are associated with KS-associated herpesvirus infection. We identified 15 virally regulated miRNAs in latently infected, nontumorigenic endothelial cells. MiR-143/145 were elevated only in KS tumors, not virally infected endothelial cells. Thus, they represent tumor-specific, rather than virus-specific, miRNAs. Because many tumor suppressor proteins are wild-type in KS and PEL, down-regulation of multiple tumor suppressor miRNAs provides a novel, alternative mechanism of transformation.
Shahab Uddin - One of the best experts on this subject based on the ideXlab platform.
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cross talk between nfkb and the pi3 kinase akt pathway can be targeted in Primary Effusion Lymphoma pel cell lines for efficient apoptosis
PLOS ONE, 2012Co-Authors: Azhar R Hussain, Leonidas C Platanias, Saeeda O Ahmed, Maqbool Ahmed, Omar S Khan, Sally Al Abdulmohsen, Khawla S Alkuraya, Shahab UddinAbstract:Background A number of constitutively activated signaling pathways play critical roles in the survival and growth of Primary Effusion Lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt’s Lymphoma and diffuse large cell B-cell Lymphoma. However, its role in Primary Effusion Lymphoma has not been fully explored. Methodology/Principal Findings We used pharmacological inhibition and gene silencing to define the role of NFkB in growth and survival of PEL cells. Inhibition of NFkB activity by Bay11-7085 resulted in decreased expression of p65 in the nuclear compartment as detected by EMSA assays. In addition, Bay11-7085 treatment caused de-phosphorylation of AKT and its downstream targets suggesting a cross-talk between NFkB and the PI3-kinase/AKT pathway. Importantly, treatment of PEL cells with Bay11-7085 led to inhibition of cell viability and induced apoptosis in a dose dependent manner. Similar apoptotic effects were found when p65 was knocked down using specific small interference RNA. Finally, co-treatment of PEL cells with suboptimal doses of Bay11-7085 and LY294002 led to synergistic apoptotic responses in PEL cells. Conclusion/Significance These data support a strong biological-link between NFkB and the PI3-kinase/AKT pathway in the modulation of anti-apoptotic effects in PEL cells. Synergistic targeting of these pathways using NFKB- and PI3-kinase/AKT- inhibitors may have a therapeutic potential for the treatment of PEL and possibly other malignancies with constitutive activation of these pathways.
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thymoquinone suppresses growth and induces apoptosis via generation of reactive oxygen species in Primary Effusion Lymphoma
Free Radical Biology and Medicine, 2011Co-Authors: Azhar R Hussain, Pulicat S Manogaran, Leonidas C Platanias, Saeeda O Ahmed, Maqbool Ahmed, Khawla S Alkuraya, Syed N Alvi, Shahab UddinAbstract:Abstract We provide evidence that thymoquinone (TQ), a natural compound isolated from Nigella sativa, induces growth inhibition and apoptosis in several Primary Effusion Lymphoma (PEL) cell lines. Our data demonstrate that TQ treatment results in down-regulation of constitutive activation of AKT via generation of reactive oxygen species (ROS) and it causes conformational changes in Bax protein, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and polyadenosine 5′-diphosphate ribose polymerase cleavage, leading to caspase-dependent apoptosis. Pretreatment of PEL cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-mediated effects. In addition, subtoxic doses of TQ sensitized PEL cells to TRAIL via up-regulation of DR5. Altogether, these findings demonstrate that TQ is a potent inducer of apoptosis in PEL cells via release of ROS. They also raise the possibility that incorporation of TQ in treatment regimens for Primary Effusion Lymphomas may provide a novel approach to sensitizing malignant cells and provide a molecular basis for such future translational efforts.
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Sanguinarine-Dependent Induction of Apoptosis in Primary Effusion Lymphoma Cells
Cancer research, 2007Co-Authors: Azhar R Hussain, Khawla S. Al-kuraya, Pulicat S Manogaran, Leonidas C Platanias, Naif A. Al-jomah, Abdul K. Siraj, Khalid Al-hussein, Jehad Abubaker, Shahab UddinAbstract:Primary Effusion Lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid). Subsequently, tBid translocates to the mitochondria causing conformational changes in Bax, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. Sanguinarine-induced release of cytochrome c results in activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, leading to induction of caspase-dependent apoptosis. In addition, we show that pretreatment of PEL cells with carbobenzoxy-Val-Ala-Asp-fluoromethylketone, a universal inhibitor of caspases, abrogates caspase and PARP activation and prevents cell death induced by sanguinarine. Moreover, treatment of PEL cells with sanguinarine down-regulates expression of inhibitor of apoptosis proteins (IAP). Finally, N-acetylcysteine, an inhibitor of ROS, inhibits sanguinarine-induced generation of ROS, up-regulation of DR5, Bax conformational changes, activation of caspase-3, and down-regulation of IAPs. Taken together, our findings suggest that sanguinarine is a potent inducer of apoptosis of PEL cells via up-regulation of DR5 and raise the possibility that this agent may be of value in the development of novel therapeutic approaches for the treatment of PEL.
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Apigenin Induces Apoptosis in Primary Effusion Lymphoma.
Blood, 2005Co-Authors: Shahab Uddin, Khawla S. Al-kurayaAbstract:The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in Primary Effusion Lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that apigenin (4′,5,7,-trihydroxyflavone), a flavonoid, induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of apigenin appear to result from suppression of the constitutively active AKT, FOXO transcription factor and GSK3. Our data also demonstrate that apigenin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5′-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for apigenin, acting as a suppressor of AKT/PKB pathway in PEL cells, leading to the induction of caspase-dependent apoptosis. Therefore, apigenin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of AKT/PKB pathway.
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curcumin suppresses growth and induces apoptosis in Primary Effusion Lymphoma
Oncogene, 2005Co-Authors: Shahab Uddin, Azhar R Hussain, Pulicat S Manogaran, Khaled Alhussein, Leonidas C Platanias, Marina I Gutierrez, Kishor BhatiaAbstract:The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in Primary Effusion Lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1). Our data also demonstrate that curcumin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for curcumin, acting as a suppressor of JAK-1 and STAT3 activation in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. Therefore, curcumin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of STAT3.
Seiji Okada - One of the best experts on this subject based on the ideXlab platform.
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targeting vegf and interleukin 6 for controlling malignant Effusion of Primary Effusion Lymphoma
Journal of Cancer Research and Clinical Oncology, 2015Co-Authors: Hiroki Goto, Harutaka Katano, Eriko Kudo, Ryusho Kariya, Manabu Taura, Seiji OkadaAbstract:Purpose Primary Effusion Lymphoma (PEL) is an aggressive subtype of non-Hodgkin Lymphoma that shows malignant Effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL.
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current status of treatment for Primary Effusion Lymphoma
Intractable & Rare Diseases Research, 2014Co-Authors: Seiji Okada, Hiroki Goto, Mihoko YotsumotoAbstract:Primary Effusion Lymphoma (PEL) is a rare and aggressive B-cell non-Hodgkin's Lymphoma that usually presents with malignant Effusions without tumor masses. An extracavitary or solid variant of PEL has also been described. Human herpes virus 8/Kaposi sarcoma-associated herpes virus (HHV-8/KSHV) is universally associated with the pathogenesis of PEL. More than 70% of cases occur with concurrent Epstein-Barr virus infection, but its relation to the pathogenesis is unknown. Patients are found in the context of immunosuppressive states (HIV-1 infection, post-organ transplantation). PEL is usually treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy with antiretroviral therapy if HIV-1 is positive. However, it is generally resistant to chemotherapy with a short median survival of less than 6 months. The optimal treatment for PEL has not been established yet. More intensive chemotherapy, such as dose-adjusted EPOCH (DA-EPOCH; etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) and CDE (cyclophosphamide, doxorubicin, etoposide) are expected to show a favorable prognosis. Recently, the molecular steps in KSHV/HHV-8-driven oncogenesis have begun to be revealed, and molecular targeting therapies such as proteasome, NF-κB, cytokines and surface antigens would provide evidence for their clinical use.
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efficacy of anti cd47 antibody mediated phagocytosis with macrophages against Primary Effusion Lymphoma
European Journal of Cancer, 2014Co-Authors: Hiroki Goto, Harutaka Katano, Ryusho Kariya, Manabu Taura, Kouki Matsuda, Yuki Kojima, Kazuhiko Kuwahara, Hirokazu Nagai, Seiji OkadaAbstract:Abstract Background Recently, the critical role of CD47 on the surface of resistant cancer cells has been proposed in their evasion of immunosurveillance. Primary Effusion Lymphoma (PEL) is a subtype of aggressive non-Hodgkin Lymphoma that shows serous Lymphomatous Effusion in body cavities, especially in advanced acquired immunodeficiency syndrome (AIDS). PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect of anti-CD47 antibody (Ab) on PEL in vitro and in vivo . Methods Surface CD47 of PEL cell lines was examined by flow cytometry. Efficacy of knocking down CD47 or anti-CD47 Ab-mediated phagocytosis against PEL was evaluated using mouse peritoneal macrophages and human macrophages in vitro . Primary PEL cells were injected intraperitoneally into NOD/Rag-2/Jak3 double-deficient (NRJ) mice to establish a direct xenograft mouse model. Results Surface CD47 of PEL cell lines was highly expressed. Knocking down CD47 and anti-CD47 Ab promoted phagocytic activities of macrophages in a CD47 expression-dependent manner in vitro . Treatment with anti-CD47 Ab inhibited ascite formation and organ invasion completely in vivo compared with control IgG-treated mice. Conclusion CD47 plays the pivotal role in the immune evasion of PEL cells in body cavities. Therapeutic antibody targeting of CD47 could be an effective therapy for PEL.
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hiv protease inhibitor lopinavir induces apoptosis of Primary Effusion Lymphoma cells via suppression of nf κb pathway
Cancer Letters, 2014Co-Authors: Ryusho Kariya, Harutaka Katano, Manabu Taura, Shinya Suzu, Hirofumi Kai, Seiji OkadaAbstract:Primary Effusion Lymphoma (PEL) is a non-Hodgkin Lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the effect of HIV protease inhibitors, Lopinavir (LPV), Ritonavir (RTV) and Darunavir (DRV) on PEL cell lines in vitro and in vivo. LPV and RTV, but not DRV induced caspase-dependent apoptosis and suppressed NF-κB activity by inhibiting IKK phosphorylation in PEL cells. In a PEL xenograft mouse model, LPV significantly inhibited the growth and invasion of PEL cells. These results suggest that LPV may have promise for the treatment and prevention of PEL, which occurs in HIV/AIDS patients.
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potent antitumor activity of zoledronic acid induced vγ9vδ2 t cells against Primary Effusion Lymphoma
Cancer Letters, 2013Co-Authors: Hiroki Goto, Harutaka Katano, Ryusho Kariya, Manabu Taura, Kouki Matsuda, Pattaravadee Srikoon, Shinichiro Hattori, Seiji OkadaAbstract:Primary Effusion Lymphoma (PEL) is a subtype of aggressive and resistant non-Hodgkin Lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of zoledronic acid (Zol)-induced Vγ9Vδ2 T cells against PEL cells in vitro and in vivo. Vγ9Vδ2 T cells recognized endogenous mevalonate metabolites and MICA/B of PEL cell lines, inducing cytotoxicity via granule exocytosis and TRAIL-mediated pathway. Vγ9Vδ2 T cells suppressed the development of PEL cells and existed in a PEL xenograft mouse model. These results show that immunotherapy with Zol-induced Vγ9Vδ2 T cells could demonstrate an efficient strategy for PEL.
Azhar R Hussain - One of the best experts on this subject based on the ideXlab platform.
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cross talk between nfkb and the pi3 kinase akt pathway can be targeted in Primary Effusion Lymphoma pel cell lines for efficient apoptosis
PLOS ONE, 2012Co-Authors: Azhar R Hussain, Leonidas C Platanias, Saeeda O Ahmed, Maqbool Ahmed, Omar S Khan, Sally Al Abdulmohsen, Khawla S Alkuraya, Shahab UddinAbstract:Background A number of constitutively activated signaling pathways play critical roles in the survival and growth of Primary Effusion Lymphoma cells (PELs) including NFkB and PI3/AKT kinase cascades. NFkBis constitutively activated in a number of malignancies, including multiple myeloma, Burkitt’s Lymphoma and diffuse large cell B-cell Lymphoma. However, its role in Primary Effusion Lymphoma has not been fully explored. Methodology/Principal Findings We used pharmacological inhibition and gene silencing to define the role of NFkB in growth and survival of PEL cells. Inhibition of NFkB activity by Bay11-7085 resulted in decreased expression of p65 in the nuclear compartment as detected by EMSA assays. In addition, Bay11-7085 treatment caused de-phosphorylation of AKT and its downstream targets suggesting a cross-talk between NFkB and the PI3-kinase/AKT pathway. Importantly, treatment of PEL cells with Bay11-7085 led to inhibition of cell viability and induced apoptosis in a dose dependent manner. Similar apoptotic effects were found when p65 was knocked down using specific small interference RNA. Finally, co-treatment of PEL cells with suboptimal doses of Bay11-7085 and LY294002 led to synergistic apoptotic responses in PEL cells. Conclusion/Significance These data support a strong biological-link between NFkB and the PI3-kinase/AKT pathway in the modulation of anti-apoptotic effects in PEL cells. Synergistic targeting of these pathways using NFKB- and PI3-kinase/AKT- inhibitors may have a therapeutic potential for the treatment of PEL and possibly other malignancies with constitutive activation of these pathways.
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thymoquinone suppresses growth and induces apoptosis via generation of reactive oxygen species in Primary Effusion Lymphoma
Free Radical Biology and Medicine, 2011Co-Authors: Azhar R Hussain, Pulicat S Manogaran, Leonidas C Platanias, Saeeda O Ahmed, Maqbool Ahmed, Khawla S Alkuraya, Syed N Alvi, Shahab UddinAbstract:Abstract We provide evidence that thymoquinone (TQ), a natural compound isolated from Nigella sativa, induces growth inhibition and apoptosis in several Primary Effusion Lymphoma (PEL) cell lines. Our data demonstrate that TQ treatment results in down-regulation of constitutive activation of AKT via generation of reactive oxygen species (ROS) and it causes conformational changes in Bax protein, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and polyadenosine 5′-diphosphate ribose polymerase cleavage, leading to caspase-dependent apoptosis. Pretreatment of PEL cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-mediated effects. In addition, subtoxic doses of TQ sensitized PEL cells to TRAIL via up-regulation of DR5. Altogether, these findings demonstrate that TQ is a potent inducer of apoptosis in PEL cells via release of ROS. They also raise the possibility that incorporation of TQ in treatment regimens for Primary Effusion Lymphomas may provide a novel approach to sensitizing malignant cells and provide a molecular basis for such future translational efforts.
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Sanguinarine-Dependent Induction of Apoptosis in Primary Effusion Lymphoma Cells
Cancer research, 2007Co-Authors: Azhar R Hussain, Khawla S. Al-kuraya, Pulicat S Manogaran, Leonidas C Platanias, Naif A. Al-jomah, Abdul K. Siraj, Khalid Al-hussein, Jehad Abubaker, Shahab UddinAbstract:Primary Effusion Lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid). Subsequently, tBid translocates to the mitochondria causing conformational changes in Bax, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. Sanguinarine-induced release of cytochrome c results in activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, leading to induction of caspase-dependent apoptosis. In addition, we show that pretreatment of PEL cells with carbobenzoxy-Val-Ala-Asp-fluoromethylketone, a universal inhibitor of caspases, abrogates caspase and PARP activation and prevents cell death induced by sanguinarine. Moreover, treatment of PEL cells with sanguinarine down-regulates expression of inhibitor of apoptosis proteins (IAP). Finally, N-acetylcysteine, an inhibitor of ROS, inhibits sanguinarine-induced generation of ROS, up-regulation of DR5, Bax conformational changes, activation of caspase-3, and down-regulation of IAPs. Taken together, our findings suggest that sanguinarine is a potent inducer of apoptosis of PEL cells via up-regulation of DR5 and raise the possibility that this agent may be of value in the development of novel therapeutic approaches for the treatment of PEL.
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curcumin suppresses growth and induces apoptosis in Primary Effusion Lymphoma
Oncogene, 2005Co-Authors: Shahab Uddin, Azhar R Hussain, Pulicat S Manogaran, Khaled Alhussein, Leonidas C Platanias, Marina I Gutierrez, Kishor BhatiaAbstract:The mechanisms that regulate induction of the antiapoptotic state and mitogenic signals in Primary Effusion Lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we found that curcumin (diferuloylmethane), a natural compound isolated from the plant Curcuma Ionga, inhibits cell proliferation and induces apoptosis in a dose dependent manner in several PEL cell lines. Such effects of curcumin appear to result from suppression of the constitutively active STAT3 through inhibition of Janus kinase 1 (JAK1). Our data also demonstrate that curcumin induces loss of mitochondrial membrane potential with subsequent release of cytochrome c and activation of caspase-3, followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. Altogether, our findings suggest a novel function for curcumin, acting as a suppressor of JAK-1 and STAT3 activation in PEL cells, leading to inhibition of proliferation and induction of caspase-dependent apoptosis. Therefore, curcumin may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of STAT3.
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inhibition of phosphatidylinositol 3 kinase akt signaling promotes apoptosis of Primary Effusion Lymphoma cells
Clinical Cancer Research, 2005Co-Authors: Shahab Uddin, Azhar R Hussain, Pulicat S Manogaran, Khaled Alhussein, Marina I Gutierrez, Amitha Wickrema, Kishor BhatiaAbstract:Purpose: Phosphatidylinositol 3′-kinase (PI3′-kinase) can be activated by the K1 protein of Kaposi sarcoma–associated herpes virus (KSHV). However, the role of PI3′-kinase in KSHV-associated Primary Effusion Lymphoma (PEL) is not known. To assess this, we studied survival and apoptosis in PEL cell lines following inhibition of PI3′-kinase. Experimental Design: Constitutive activation of several targets of PI3-kinase and apoptotic proteins were determined by Western blot analysis using specific antibodies. We used LY294002 to block PI3′-kinase/AKT activation and assess apoptosis by flow cytometric analysis. Results: Blocking PI3′-kinase induced apoptosis in PEL cells, including BC1, BC3, BCBL1, and HBL6, whereas BCP1 was refractory to LY294002-induced apoptosis. LY294002-induced apoptosis did not seem to involve Fas/Fas-L but had an additive effect to CH11-mediated apoptosis. We also show that AKT/PKB is constitutively activated in all PELs and treatment with LY294002 causes complete dephosphorylation in all cell lines except BCP1 where a residual AKT phosphorylation remained after 24 hours of treatment. FKHR and GSK3 were also constitutively phosphorylated in PELs and treatment with LY294002 caused their dephosphorylation. Although inhibition of PI3′-kinase induced cleavage of BID in all cell lines, cytochrome c was released from the mitochondria and caspase-9 and caspase-3 were activated in LY294002-induced apoptotic BC1 but not in resistant BCP1. Similarly, XIAP, a target of AKT, was down-regulated after LY294002 treatment only in sensitive PEL cells. Conclusions : Our data show that the PI3′-kinase pathway plays a major role in survival of PEL cells and suggest that this cascade may be a promising target for therapeutic intervention in Primary Effusion Lymphomas.
Harutaka Katano - One of the best experts on this subject based on the ideXlab platform.
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fumagillin a potent angiogenesis inhibitor induces kaposi sarcoma associated herpesvirus replication in Primary Effusion Lymphoma cells
Biochemical and Biophysical Research Communications, 2015Co-Authors: Takayuki Kanno, Taeko Uehara, Madori Osawa, Hitomi Fukumoto, Sohtaro Mine, Keiji Ueda, Hideki Hasegawa, Harutaka KatanoAbstract:Abstract Kaposi sarcoma and Primary Effusion Lymphoma cells are infected with Kaposi sarcoma-associated herpesvirus (KSHV), predominantly in the latent form, and KSHV replication is observed rarely. Angiogenesis plays a crucial role in the pathogenesis of both Kaposi sarcoma and Primary Effusion Lymphoma. In this study, we found that fumagillin, a potent angiogenesis inhibitor, induced replication of KSHV in Primary Effusion Lymphoma cell lines. The transcript and protein product of replication transcriptional activator (RTA) were induced by 1–10 μM fumagillin at 24 and 48 h, respectively. Western blot analysis demonstrated that 10 μM fumagillin induced not only RTA expression but also other KSHV-encoded lytic proteins. A real-time PCR array detecting KSHV gene expression demonstrated that the expression profiles of KSHV induced by fumagillin were similar to those induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), but the amounts of each transcript were lower than those induced by TPA. Finally, real-time PCR demonstrated an increase in that viral DNA copy number per cell in fumagillin-stimulated Primary Effusion Lymphoma cell lines, indicating replication of KSHV. In addition to TPA, 10 μM fumagillin resulted in growth inhibition of Primary Effusion Lymphoma cell lines. These observations suggest that an angiogenesis inhibitor is an agent with potent effects on cell growth and KSHV reactivation in Primary Effusion Lymphoma cells.
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targeting vegf and interleukin 6 for controlling malignant Effusion of Primary Effusion Lymphoma
Journal of Cancer Research and Clinical Oncology, 2015Co-Authors: Hiroki Goto, Harutaka Katano, Eriko Kudo, Ryusho Kariya, Manabu Taura, Seiji OkadaAbstract:Purpose Primary Effusion Lymphoma (PEL) is an aggressive subtype of non-Hodgkin Lymphoma that shows malignant Effusion most commonly seen in advanced AIDS patients. In this study, we clarified the potential role of VEGF and IL-6 in PEL fluid retention and evaluated the efficacy of humanized anti-VEGF monoclonal antibody (mAb), bevacizumab, and humanized anti-IL-6 receptor mAb, tocilizumab, against PEL.
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efficacy of anti cd47 antibody mediated phagocytosis with macrophages against Primary Effusion Lymphoma
European Journal of Cancer, 2014Co-Authors: Hiroki Goto, Harutaka Katano, Ryusho Kariya, Manabu Taura, Kouki Matsuda, Yuki Kojima, Kazuhiko Kuwahara, Hirokazu Nagai, Seiji OkadaAbstract:Abstract Background Recently, the critical role of CD47 on the surface of resistant cancer cells has been proposed in their evasion of immunosurveillance. Primary Effusion Lymphoma (PEL) is a subtype of aggressive non-Hodgkin Lymphoma that shows serous Lymphomatous Effusion in body cavities, especially in advanced acquired immunodeficiency syndrome (AIDS). PEL is resistant to conventional chemotherapy and has a poor prognosis. In this study, we evaluated the effect of anti-CD47 antibody (Ab) on PEL in vitro and in vivo . Methods Surface CD47 of PEL cell lines was examined by flow cytometry. Efficacy of knocking down CD47 or anti-CD47 Ab-mediated phagocytosis against PEL was evaluated using mouse peritoneal macrophages and human macrophages in vitro . Primary PEL cells were injected intraperitoneally into NOD/Rag-2/Jak3 double-deficient (NRJ) mice to establish a direct xenograft mouse model. Results Surface CD47 of PEL cell lines was highly expressed. Knocking down CD47 and anti-CD47 Ab promoted phagocytic activities of macrophages in a CD47 expression-dependent manner in vitro . Treatment with anti-CD47 Ab inhibited ascite formation and organ invasion completely in vivo compared with control IgG-treated mice. Conclusion CD47 plays the pivotal role in the immune evasion of PEL cells in body cavities. Therapeutic antibody targeting of CD47 could be an effective therapy for PEL.
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hiv protease inhibitor lopinavir induces apoptosis of Primary Effusion Lymphoma cells via suppression of nf κb pathway
Cancer Letters, 2014Co-Authors: Ryusho Kariya, Harutaka Katano, Manabu Taura, Shinya Suzu, Hirofumi Kai, Seiji OkadaAbstract:Primary Effusion Lymphoma (PEL) is a non-Hodgkin Lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the effect of HIV protease inhibitors, Lopinavir (LPV), Ritonavir (RTV) and Darunavir (DRV) on PEL cell lines in vitro and in vivo. LPV and RTV, but not DRV induced caspase-dependent apoptosis and suppressed NF-κB activity by inhibiting IKK phosphorylation in PEL cells. In a PEL xenograft mouse model, LPV significantly inhibited the growth and invasion of PEL cells. These results suggest that LPV may have promise for the treatment and prevention of PEL, which occurs in HIV/AIDS patients.
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hippuristanol reduces the viability of Primary Effusion Lymphoma cells both in vitro and in vivo
Marine Drugs, 2013Co-Authors: Chie Ishikawa, Harutaka Katano, Junichi Tanaka, Masachika Senba, Naoki MoriAbstract:Primary Effusion Lymphoma (PEL) caused by Kaposi’s sarcoma-associated herpesvirus (also known as human herpesvirus-8) shows serious Lymphomatous Effusion in body cavities. PEL is difficult to treat and there is no standard treatment strategy. Hippuristanol is extracted from Okinawan coral Isis hippuris, and inhibits translational initiation by blocking eukaryotic initiation factor 4A, an ATP-dependent RNA helicase, binding to mRNA. Recently, there has been much interest in targeting translation initiation as an anticancer therapy. Here, we show that treatment of PEL cell lines with hippuristanol resulted in cell cycle arrest at G1 phase, and induced caspases activation and apoptosis. Hippuristanol also reduced the expression of cyclin D2, CDK2, CDK4, CDK6 and prosurvival XIAP and Mcl-1 proteins. Activation of activator protein-1, signal transducers and activators of transcription protein 3 and Akt pathways plays a critical role in the survival and growth of PEL cells. Hippuristanol suppressed the activities of these three pathways by inhibiting the expression of JunB, JunD, c-Fos, signal transducers and activators of transcription protein 3 and Akt proteins. In a xenograft mouse model that showed ascites and diffused organ invasion of PEL cells, treatment with hippuristanol significantly inhibited the growth and invasion of PEL cells compared with untreated mice. The results of the in vitro and in vivo experiments underline the potential usefulness of hippuristanol in the treatment of PEL.