Current status of treatment for primary effusion lymphoma

Okada, Seiji; Goto, Hiroki; Yotsumoto, Mihoko

doi:10.5582/irdr.2014.01010

Cited by 99 publications

(113 citation statements)

References 82 publications

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“…PEL is an aggressive lymphoma caused by KSHV, and is resistant to chemotherapy regimens, such as CHOP and R-CHOP (26). Therefore, the development of novel and effective drugs for PEL is required.…”

Section: Diallyl Trisulfide Induces Apoptosis By Suppressing Nf-κb Simentioning

confidence: 99%

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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Abstract. The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL. IntroductionPrimary effusion lymphoma (PEL, also termed body-cavitybased lymphoma) is a malignant B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV, also named HHV-8) in immunosuppressed individuals, such as AIDS patients or those that have undergone organ transplantation (1,2). PEL is a subtype of non-Hodgkin's lymphoma and is characterized by lymphomatous effusions of pleural and abdominal cavities. KSHV is a rhadinovirus of the γ-herpesvirus subfamily and is closely related to herpesvirus Saimiri and Epstein-Barr virus (EBV). KSHV is the causative agent of Kaposi's sarcoma and AIDS-related lymphoproliferative disorders, such as PEL and multicentric Castleman's disease (3). Similar to other herpesviruses, KSHV has two life cycles (latency and lytic replication). The KSHV genome circularizes and forms a double-stranded DNA, the episome, in the nucleus of PEL cells during latent infection. To establish a latent infection, KSHV expresses several viral genes, including latency-associated nuclear antigen (LANA), v-FLIP, v-cyclin, kaposin and microRNAs, in PEL cells. LANA is required for the replication and maintenance of viral DNA, and contributes to KSHV-associated oncogenesis through interaction with cellular molecules, such as p53, Rb and GSK-3. These viral proteins and RNA manipulate cellular signaling pathways, includ...

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Section: Diallyl Trisulfide Induces Apoptosis By Suppressing Nf-κb Simentioning

confidence: 99%

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Shigemi

Furukawa

Hosokawa

et al. 2015

International Journal of Oncology

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“…Like other herpesviruses, KSHV exhibits a dual-phase life cycle that includes latency and lytic infection (3). During latency, the KSHV episome expresses a limited number of viral genes that mediate multiple functions, including maintaining viral genomes, repressing viral lytic gene expression, promoting proliferation of infected cells, and perturbing host immune surveillance (4)(5)(6). Periodic switching from latency to the lytic phase results in an orderly expression of a large number of viral genes to produce infectious virions.…”

mentioning

confidence: 99%

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

King

Barbachano-Guerrero

et al. 2015

J Virol

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Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phasedirected therapies for herpesviruses. IMPORTANCELytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses, however, a substantial fraction of latently infected cells are resistant to lytic-phase-inducing stimuli. Investigating the molecular basis for this refractory state is essential for understanding how the virus persists and how it causes disease and to guide efforts to improve treatment of KSHV-mediated diseases. We found that, like two other herpesviruses, EBV and HSV-1, KSHV exploits the cellular transcription factor STAT3 to regulate the susceptibility of latently infected cells to lytic triggers. These findings highlight a common STAT3-centered strategy used by herpesviruses to maintain persistence in their hosts while also revealing a key molecule to pursue while devising methods to improve herpesvirus lytic-phase-directed therapies.T he oncogenic human gammaherpesvirus human herpesvirus 8 (HHV-8), widely known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of three human malignancies: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). Like other herpesviruses, KSHV exhi...

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“…PEL has a strong prognosis for mortality during the early phase, whereas the literature includes numerous reports of favorable responses to chemotherapy in patients with PEL‐LL 7. It has been reported that etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin (DA‐EPOCH therapy or CDE therapy), or ganciclovir is effective for PEL,8, 9 but treatment‐based evidence for PEL and PEL‐LL has not yet been established. Expecting an effect of rituximab to CD20 antigen, we performed R‐CHOP therapy 10.…”

Section: Discussionmentioning

confidence: 99%

A unique case of primary effusion lymphoma‐like lymphoma showing disappearance and recurrence of the body cavity effusion

Koeda

Sato

Matsumoto

et al. 2017

J of Gen and Family Med

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Primary effusion lymphoma‐like lymphoma (PEL‐LL) is a rare B‐cell lymphoma that the etiology remains unclear. We describe a case of PEL‐LL with a pleuropericardial effusion. Diagnosis required long period of time as it followed a unique progress of disappearance and recurrence of the body cavity effusion. We finally had a diagnosis of B‐cell lymphoma by the immunocytochemistry of effusion using the cell block procedure. Authors consider that it is valuable to actively try the cell block procedure at the time of the first drainage for early diagnosis, if the body cavity effusion due to the malignancy is suspected.

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Current status of treatment for primary effusion lymphoma

Cited by 99 publications

References 82 publications

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

A unique case of primary effusion lymphoma‐like lymphoma showing disappearance and recurrence of the body cavity effusion

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