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: Shanique K E Edwards, Carissa R Moore, Yan Liu, Sukhdeep Grewal, Lori R Covey, Ping Xie
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 481 (Oct 16 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 24131623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 3-ingenyl angelate
• Antibiotics, Antineoplastic
• Diterpenes
• Proto-Oncogene Proteins c-myc
• TNF Receptor-Associated Factor 3
• Doxorubicin
• N-benzyladriamycin-14-valerate
• Protein Kinase C-delta
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Diterpenes (administration & dosage, pharmacology)
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacology)
• Enzyme Activation (drug effects)
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Genetic Vectors (genetics)
• Humans
• Isografts
• Lentivirus (genetics)
• Lymphoma, B-Cell (drug therapy, genetics, metabolism, mortality)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinases (metabolism)
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Protein Kinase C-delta (metabolism)
• Protein Transport
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-myc (genetics)
• TNF Receptor-Associated Factor 3 (deficiency, genetics, metabolism)
• Transduction, Genetic