title: A purine scaffold HSP90 inhibitor BIIB021 has selective activity against KSHV-associated primary effusion lymphoma and blocks vFLIP K13-induced NF-κB.
abstract: OBJECTIVE
  Kaposi sarcoma-associated herpes virus (KSHV)-associated primary effusion lymphomas (PEL) have extremely poor prognosis when treated with conventional chemotherapy. KSHV-encoded viral FLICE-inhibitory protein (vFLIP) K13 binds to the IkappaB kinase (IKK) complex to constitutively activate the NF-κB pathway, which has been shown to be essential for the survival and proliferation of PEL cells. The molecular chaperone HSP90 is a component of the IKK complex and is required for its activity.
  
  
  METHODS
  We have analyzed the effect of HSP90 inhibitors on the survival and proliferation of PEL cells and on the activity of the NF-κB pathway.
  
  
  RESULTS
  We show that BIIB021, a purine scaffold-based orally administrable HSP90 inhibitor, shows preferential cytotoxicity toward PEL cells as compared with non-PEL cells. The cytotoxic effect of BIIB021 against PEL was associated with induction of cell-cycle arrest and apoptosis. BIIB021 blocked the expression of a number of cellular proteins involved in the regulation of cell cycle and apoptosis. BIIB021 also blocked constitutive NF-κB activity present in PEL cells, in part, by blocking the interaction of vFLIP K13 with the IKK complex subunits. In a xenograft model of PEL, BIIB021 significantly reduced tumor growth.
  
  
  CONCLUSIONS
  BIIB021 blocks constitutive NF-κB activity in PEL and shows preferential antitumor activity against PEL in vitro and in vivo. BIIB021 may be a promising agent for treatment of PEL.
authors.affiliation: Authors' Affiliation: Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Gopalakrishnan
authors.forename: Hittu
authors.initials: H
authors.lastname: Matta
authors.forename: Preet M
authors.initials: PM
authors.lastname: Chaudhary
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006566:Herpesviridae Infections / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011687:Purines / Q000737:chemistry; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C521963:6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-ylamine; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D011687:Purines; D011725:Pyridines; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D000225:Adenine; C030985:purine