PMID- 18850009
OWN - NLM
STAT- MEDLINE
DCOM- 20090507
LR  - 20151119
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 28
IP  - 2
DP  - 2009 Jan 15
TI  - Bortezomib overcomes cell-adhesion-mediated drug resistance through 
      downregulation of VLA-4 expression in multiple myeloma.
PG  - 231-42
LID - 10.1038/onc.2008.385 [doi]
AB  - Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug 
      resistance (CAM-DR). In this study, we performed functional screening using short 
      hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using 
      four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and 
      primary myeloma cells, we identified CD29 (beta1-integrin), CD44, CD49d 
      (alpha4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 
      (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as 
      major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but 
      not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to 
      bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using 
      blocking antibodies yielded almost identical results. Bortezomib was relatively 
      resistant to CAM-DR because of its ability to specifically downregulate CD49d 
      expression. This property was unique to bortezomib and was not observed in other 
      anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of 
      myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 
      plays a critical role in CAM-DR of MM cells. The combination of bortezomib with 
      conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.
FAU - Noborio-Hatano, K
AU  - Noborio-Hatano K
AD  - Division of Hematology, Department of Internal Medicine, Jichi Medical 
      University, Tochigi, Japan.
FAU - Kikuchi, J
AU  - Kikuchi J
FAU - Takatoku, M
AU  - Takatoku M
FAU - Shimizu, R
AU  - Shimizu R
FAU - Wada, T
AU  - Wada T
FAU - Ueda, M
AU  - Ueda M
FAU - Nobuyoshi, M
AU  - Nobuyoshi M
FAU - Oh, I
AU  - Oh I
FAU - Sato, K
AU  - Sato K
FAU - Suzuki, T
AU  - Suzuki T
FAU - Ozaki, K
AU  - Ozaki K
FAU - Mori, M
AU  - Mori M
FAU - Nagai, T
AU  - Nagai T
FAU - Muroi, K
AU  - Muroi K
FAU - Kano, Y
AU  - Kano Y
FAU - Furukawa, Y
AU  - Furukawa Y
FAU - Ozawa, K
AU  - Ozawa K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081013
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Antibodies)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Boronic Acids)
RN  - 0 (CDw49d)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Integrin alpha Chains)
RN  - 0 (Integrin alpha4beta1)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Pyrazines)
RN  - 143198-26-9 (Integrin alpha4)
RN  - 5J49Q6B70F (Vincristine)
RN  - 69G8BD63PP (Bortezomib)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Antibodies/pharmacology
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Boronic Acids/*pharmacology
MH  - Bortezomib
MH  - Cell Adhesion/*physiology
MH  - Cell Adhesion Molecules/physiology
MH  - Cell Line, Tumor/metabolism
MH  - Dexamethasone/pharmacology
MH  - Down-Regulation
MH  - Doxorubicin/pharmacology
MH  - Drug Resistance, Neoplasm/*drug effects/physiology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - Integrin alpha Chains/biosynthesis/genetics/*physiology
MH  - Integrin alpha4/biosynthesis/genetics/*physiology
MH  - Integrin alpha4beta1/*physiology
MH  - Multiple Myeloma/drug therapy/*metabolism
MH  - Neoplasm Proteins/biosynthesis/genetics/*physiology
MH  - Pyrazines/*pharmacology
MH  - Vincristine/pharmacology
EDAT- 2008/10/14 09:00
MHDA- 2009/05/08 09:00
CRDT- 2008/10/14 09:00
PHST- 2008/10/14 09:00 [pubmed]
PHST- 2009/05/08 09:00 [medline]
PHST- 2008/10/14 09:00 [entrez]
AID - onc2008385 [pii]
AID - 10.1038/onc.2008.385 [doi]
PST - ppublish
SO  - Oncogene. 2009 Jan 15;28(2):231-42. doi: 10.1038/onc.2008.385. Epub 2008 Oct 13.