Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF‐κB pathway

Abstract

Primary effusion lymphoma (PEL) is a unique and recently identified non-Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma-associated herpes virus (KSHV/HHV-8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)-jB pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL-1, TY-1 and RM-P1), in vitro and in vivo. An methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1-10 lg/ml). CEP also inhibited NF-jB activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL-1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NF-jB could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. ' 2009 UICC

Kaposi's Sarcoma-Associated Herpesvirus-Positive Primary Effusion Lymphoma Tumor Formation in NOD/SCID Mice Is Inhibited by Neomycin and Neamine Blocking Angiogenin's Nuclear Translocation

“…Similar to our results, blocking the NF-B pathway with Bay11-7082 has been shown to prevent or delay PEL tumor growth in NOD/SCID mice and prolong their disease-free survival (66). The therapeutic potential of blocking the NF-B pathway has been confirmed by blocking the proteosome with Bortezomib, using the new NF-B inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), or using the biscoclaurine alkaloid cepharanthine (67)(68)(69)(70)(71). In all these studies, blocking the NF-B pathway induced the apoptosis of PEL.…”

Inhibitory effect of cepharanthine on dendritic cell activation and function

“…NF-κB is known to play a key role in upregulating costimulatory molecules and MHC class I, and induction of inflammatory cytokines [3]. Although CEP exerts its antitumor activity through the inhibition of NF-κB, its molecular mechanism in inhibiting NF-κB has not been fully elucidated yet [16][17][18]. CEP did not affect the degradation of IκB, an inhibitory molecule of NF-κB (data not shown).…”

Therapeutic effects of γ-irradiation in a primary effusion lymphoma mouse model

“…vfLIPmediated Nf-κB activation is necessary for the survival of PEL cells, and may cause them to become chemoresistant. Thus, the Nf-κB pathway represents an appropriate target for the molecular therapy of PEL, and several Nf-κB inhibitors are already potential candidates (24)(25)(26). One of these candidates, the proteasome inhibitor bortezomib, has been shown to inhibit Nf-κB activity and induce the apoptosis of PEL cell lines in vitro (27,28); however, bortezomib failed to control the progression of PEL in a clinical trial (29), indicating that …”

“…Animal models of human malignancies have been applied to study the nature of cancer stem cells and to assess the therapeutic effects of novel therapeutic strategies against malignant neoplasms (33,34). In particular, the recent introduction of severe immunodeficient mice has enabled us to develop mice mimicking hematologic malignancies (26,35). In this study, we used PEL-xenografted Rag2/ Jak3 double-deficient mice resembling the diffuse nature of human PEL, which is quite useful to assess the therapeutic efficacy of γ-irradiation in mice in a hematological malignancy model.…”