Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
CXCL 12 and CXCR 7 are relevant targets to reverse cell adhesion‐mediated drug resistance in multiple myeloma
Ist Teil von
British journal of haematology, 2017-10, Vol.179 (1), p.36-49
Erscheinungsjahr
2017
Quelle
Wiley Online Library
Beschreibungen/Notizen
Summary
Cell adhesion‐mediated drug resistance (
CAM
‐
DR
) by the bone marrow (
BM
) is fundamental to multiple myeloma (
MM
) propagation and survival. Targeting
BM
protection to increase the efficacy of current anti‐myeloma treatment has not been extensively pursued. To extend the understanding of
CAM
‐
DR
, we hypothesized that the cytotoxic effects of novel anti‐myeloma agents may be abrogated by the presence of
BM
stroma cells (
BMSC
s) and restored by addition of the
CXCL
12 antagonist
NOX
‐A12 or the
CXCR
4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti‐myeloma agents alone, with
BMSC
s and when combined with plerixafor or
NOX
‐A12. We verified
CXCR
4,
CD
49d (also termed
ITGA
4) and
CD
44 as essential mediators of
BM
adhesion on
MM
cells. Additionally, we show that
CXCR
7, the second receptor of stromal‐derived‐factor‐1 (
CXCL
12), is highly expressed in active
MM
. Co‐culture proved that co‐treatment with plerixafor or
NOX
‐A12, the latter inhibiting
CXCR
4 and
CXCR
7, functionally interfered with
MM
chemotaxis to the
BM
. This led to the resensitization of
MM
cells to the anti‐myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/
II
study,
NOX
‐A12 was tested in combination with bortezomib‐dexamethasone, underlining the feasibility of
NOX
‐A12 as an active add‐on agent to antagonize myeloma
CAM
‐
DR
.
Sprache
Englisch
Identifikatoren
ISSN: 0007-1048
eISSN: 1365-2141
DOI: 10.1111/bjh.14807
Titel-ID: cdi_crossref_primary_10_1111_bjh_14807
Format
–
Weiterführende Literatur
Empfehlungen zum selben Thema automatisch vorgeschlagen von bX