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- Title
N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma.
- Authors
Edwards, Shanique K.; Moore, Carissa R.; Yan Liu; Grewal, Sukhdeep; Covey, Lori R.; Ping Xie; Edwards, Shanique K E; Liu, Yan; Xie, Ping
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
ANTHRACYCLINES; LYMPHOMA treatment; MULTIPLE myeloma treatment; PHARMACODYNAMICS; TUMOR suppressor proteins; CELL lines; LABORATORY mice; CELLULAR signal transduction; ANIMAL experimentation; ANTINEOPLASTIC antibiotics; APOPTOSIS; B cell lymphoma; BIOCHEMISTRY; BIOLOGICAL models; BIOLOGICAL transport; CARRIER proteins; CELL nuclei; CELL physiology; COMPARATIVE studies; DOXORUBICIN; GENE expression; GENES; GENETICS; HYDROCARBONS; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; METABOLISM; MICE; MULTIPLE myeloma; PROTEINS; RESEARCH; RESEARCH funding; RETROVIRUSES; TRANSFERASES; TRANSPLANTATION of organs, tissues, etc.; EVALUATION research
- Publication
BMC Cancer, 2013, Vol 13, Issue 1, p1
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/1471-2407-13-481