title: N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma.
abstract: BACKGROUND
  TRAF3, a new tumor suppressor identified in human non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), induces PKCδ nuclear translocation in B cells. The present study aimed to evaluate the therapeutic potential of two PKCδ activators, N-Benzyladriamycin-14-valerate (AD 198) and ingenol-3-angelate (PEP005), on NHL and MM.
  
  
  METHODS
  In vitro anti-tumor activities of AD 198 and PEP005 were determined using TRAF3-/- mouse B lymphoma and human patient-derived MM cell lines as model systems. In vivo therapeutic effects of AD 198 were assessed using NOD SCID mice transplanted with TRAF3-/- mouse B lymphoma cells. Biochemical studies were performed to investigate signaling mechanisms induced by AD 198 or PEP005, including subcellular translocation of PKCδ.
  
  
  RESULTS
  We found that AD 198 exhibited potent in vitro and in vivo anti-tumor activity on TRAF3-/- tumor B cells, while PEP005 displayed contradictory anti- or pro-tumor activities on different cell lines. Detailed mechanistic investigation revealed that AD 198 did not affect PKCδ nuclear translocation, but strikingly suppressed c-Myc expression and inhibited the phosphorylation of ERK, p38 and JNK in TRAF3-/- tumor B cells. In contrast, PEP005 activated multiple signaling pathways in these cells, including PKCδ, PKCα, PKCε, NF-κB1, ERK, JNK, and Akt. Additionally, AD198 also potently inhibited the proliferation/survival and suppressed c-Myc expression in TRAF3-sufficient mouse and human B lymphoma cell lines. Furthermore, we found that reconstitution of c-Myc expression conferred partial resistance to the anti-proliferative/apoptosis-inducing effects of AD198 in human MM cells.
  
  
  CONCLUSIONS
  AD 198 and PEP005 have differential effects on malignant B cells through distinct biochemical mechanisms. Our findings uncovered a novel, PKCδ-independent mechanism of the anti-tumor effects of AD 198, and suggest that AD 198 has therapeutic potential for the treatment of NHL and MM involving TRAF3 inactivation or c-Myc up-regulation.
authors.forename: Shanique K E
authors.initials: SK
authors.lastname: Edwards
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Moore
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Sukhdeep
authors.initials: S
authors.lastname: Grewal
authors.forename: Lori R
authors.initials: LR
authors.lastname: Covey
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Nelson Labs Room B336, Piscataway, NJ 08854, USA. xiep@rci.rutgers.edu.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D064596:Isografts; D016086:Lentivirus / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: C486592:3-ingenyl angelate; D000903:Antibiotics, Antineoplastic; D004224:Diterpenes; D016271:Proto-Oncogene Proteins c-myc; D048008:TNF Receptor-Associated Factor 3; D004317:Doxorubicin; C046808:N-benzyladriamycin-14-valerate; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases