PMID- 11468181
OWN - NLM
STAT- MEDLINE
DCOM- 20010913
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 98
IP  - 3
DP  - 2001 Aug 1
TI  - TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in 
      multiple myeloma: therapeutic applications.
PG  - 795-804
AB  - Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. 
      Preclinical in vitro and in vivo evaluations were performed to assess the 
      potential therapeutic applications of human recombinant tumor necrosis factor 
      (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. 
      TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority 
      of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), 
      doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the 
      survival effect of interleukin 6 on MM cells and did not affect the survival of 
      peripheral blood and bone marrow mononuclear cells and purified B cells from 
      healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and 
      flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM 
      activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM 
      cells; TRAIL (500 microg intraperitoneally daily for 14 days) was well tolerated 
      and significantly suppressed the growth of plasmacytomas. Dox up-regulated the 
      expression of the TRAIL receptor death receptor 5 (DR5) and synergistically 
      enhanced the effect of TRAIL not only against MM cells sensitive to, but also 
      against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor 
      (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear 
      translocation and transcriptional activity of NF-kappaB) or the proteasome 
      inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against 
      TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 
      and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL 
      by either Dox, SN50, or PS-341. These preclinical studies suggest that 
      TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for 
      clinical trials of TRAIL-based treatment regimens to improve outcome in patients 
      with MM. (Blood. 2001;98:795-804)
FAU - Mitsiades, C S
AU  - Mitsiades CS
AD  - Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber 
      Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
FAU - Treon, S P
AU  - Treon SP
FAU - Mitsiades, N
AU  - Mitsiades N
FAU - Shima, Y
AU  - Shima Y
FAU - Richardson, P
AU  - Richardson P
FAU - Schlossman, R
AU  - Schlossman R
FAU - Hideshima, T
AU  - Hideshima T
FAU - Anderson, K C
AU  - Anderson KC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 0 (Tnfsf10 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins
MH  - B-Lymphocytes/drug effects
MH  - Dexamethasone/pharmacology/therapeutic use
MH  - Drug Evaluation, Preclinical
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - Humans
MH  - Interleukin-6/pharmacology
MH  - Membrane Glycoproteins/administration & dosage/*pharmacology
MH  - Mice
MH  - Multiple Myeloma/*drug therapy
MH  - NF-kappa B/antagonists & inhibitors/pharmacology
MH  - Neoplasm Transplantation
MH  - Plasmacytoma/drug therapy
MH  - Receptors, Tumor Necrosis Factor/metabolism
MH  - TNF-Related Apoptosis-Inducing Ligand
MH  - Transplantation, Heterologous
MH  - Tumor Cells, Cultured/drug effects
MH  - Tumor Necrosis Factor-alpha/administration & dosage/*pharmacology
EDAT- 2001/07/27 10:00
MHDA- 2001/09/14 10:01
CRDT- 2001/07/27 10:00
PHST- 2001/07/27 10:00 [pubmed]
PHST- 2001/09/14 10:01 [medline]
PHST- 2001/07/27 10:00 [entrez]
AID - S0006-4971(20)48082-6 [pii]
AID - 10.1182/blood.v98.3.795 [doi]
PST - ppublish
SO  - Blood. 2001 Aug 1;98(3):795-804. doi: 10.1182/blood.v98.3.795.