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

Abstract

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-kappaB activation. Dehydroxymethylepoxyquinomicin (DHMEQ) is a new NF-kappaB inhibitor and is effective on various tumor cells with constitutively activated NF-kappaB. 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-kappaB with subcomponents of p50 and p65 in PEL cell lines. DHMEQ quickly and transiently abrogated NF-kappaB 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-kappaB target genes, such as interleukin-6 (IL6), Myc, chemokine (C-C motif) receptor 5 (CCR5) and NF-kappaB1, 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-kappaB 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-kappaB 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.

• Authors: Nazanin Dabaghmanesh, Aiko Matsubara, Ariko Miyake, Kazumi Nakano, Takaomi Ishida, Harutaka Katano, Ryoichi Horie, Kazuo Umezawa, Toshiki Watanabe
• Journal: Cancer science (Cancer Sci) Vol. 100 Issue 4 Pg. 737-46 (Apr 2009) ISSN: 1349-7006 [Electronic] England
• PMID: 19469019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Cyclohexanones
• NF-kappa B
• dehydroxymethylepoxyquinomicin
• Caspase 3
• Caspase 8
• Caspase 9

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclohexanones (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• HeLa Cells
• Herpesvirus 8, Human (metabolism)
• Humans
• In Situ Nick-End Labeling
• Jurkat Cells
• K562 Cells
• Lymphoma, Primary Effusion (drug therapy, prevention & control, virology)
• NF-kappa B (antagonists & inhibitors)
• Time Factors