Transient inhibition of NF-κB by DHMEQ induces cell death of primary effusion lymphoma without HHV-8 reactivation

• Published in: Cancer science Vol. 100; no. 4; pp. 737 - 746
• Main Authors: Dabaghmanesh, Nazanin, Matsubara, Aiko, Miyake, Ariko, Nakano, Kazumi, Ishida, Takaomi, Katano, Harutaka, Horie, Ryoichi, Umezawa, Kazuo, Watanabe, Toshiki
• Format: Journal Article
• Language: English
• Published: Melbourne, Australia Blackwell Publishing Asia 01.04.2009; Blackwell
• Subjects: Biological and medical sciences; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Original; Tumors; Gammaherpesvirinae; Reactivation; Herpesviridae; B cell neoplasm; Malignant hemopathy; Non Hodgkin lymphoma; Transitory; Virus; Human herpesvirus 8; Cancerology; Cell death; Lymphoproliferative syndrome; Inhibitor; Transcription factor NFκB; Primary effusion lymphoma; Cancer; Apoptosis
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2009.01083.x

Primary effusion lymphoma (PEL) is a refractory malignancy caused by human herpes virus 8 (HHV‐8) in immunocompromised individuals. The tumor cells of PEL are characterized by constitutive NF‐κB activation. Dehydroxymethylepoxyquinomicin (DHMEQ) is a new NF‐κB inhibitor and is effective on various tumor cells with constitutively activated NF‐κB. Thus, in search for a new therapeutic modality of PEL, we examined the effect of DHMEQ on PEL cells. We confirmed constitutive activation of NF‐κB with subcomponents of p50 and p65 in PEL cell lines. DHMEQ quickly and transiently abrogated NF‐κB activation and reduced the cell viability in dose‐ and time‐dependent manners, inducing apoptosis through activation of both mitochondrial and membrane pathways. Array analysis revealed that DHMEQ down‐regulated expression levels of NF‐κB target genes, such as interleukin‐6 (IL6), Myc, chemokine (C‐C motif) receptor 5 (CCR5) and NF‐κB1, whereas it up‐regulated expression levels of some genes involved in apoptosis, and cell cycle arrest. DHMEQ did not reactivate HHV‐8 lytic genes, indicating that NF‐κB inhibition by DHMEQ did not induce virus replication. DHEMQ rescued CB‐17 SCID mice xenografted with PEL cells, reducing the gross appearance of effusion. Thus, DHMEQ transiently abrogated the NF‐κB activation, irreversibly triggering the apoptosis cascade without HHV‐8 reactivation. In addition, DHMEQ could rescue the PEL‐xenograft mice. Therefore, we suggest DHMEQ as a promising candidate for molecular target therapy of the PEL. (Cancer Sci 2009; 100: 737–746)