TY - JOUR
T1 - The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide
AU - Abeltino, Manuela
AU - Bonomini, Sabrina
AU - Bolzoni, Marina
AU - Storti, Paola
AU - Colla, Simona
AU - Todoerti, Katia
AU - Agnelli, Luca
AU - Neri, Antonino
AU - Rizzoli, Vittorio
AU - Giuliani, Nicola
N1 - Funding Information:
This work was supported by grants from Novartis Italia , the International Myeloma Foundation (IMF) (senior grant 2009 ), the Italian Ministry of Health (Progetti Regione Emilia Romagna) and from AIRC (grant IG2009-8530 ). NG and VR were supported by a grant from Novartis Italia. The Authors would like to thank Alessandra Leporati for secretarial and technical assistance.
PY - 2011/1
Y1 - 2011/1
N2 - Objective: Multiple myeloma (MM) cells are extremely resistant to drug-induced apoptosis due to both intrinsic- and bone marrow (BM) microenvironment-dependent drug resistance particularly supported by bone cells. Growing evidence suggest that the osteoclast inhibitor zoledronic acid (ZOL) exerts both indirect and direct anti-tumoral effects, including an in vitro proapoptotic effect on MM cells, although this property has not yet been clearly observed in MM patients. Materials and Methods: In this study, we attempt to better define the cytotoxic effect of ZOL on MM cells in order to identify novel drug combinations able to potentiate its proapoptotic effect. Results: Our data shows that ZOL at concentrations ranging from 10 to 100 μM was able to induce MM cell apoptosis overcoming the prosurvival effect of both stromal cells and osteoclasts and independent of the intrinsic bortezomib resistance of MM cells. Interestingly, we found that the capacity of ZOL to induce apoptosis in bortezomib-resistant cells was associated with a downregulation of the proapoptotic molecule myeloid cell leukemia-1. A transcriptional analysis by microarray was also performed to identify genes specifically modulated by ZOL in bortezomib-resistant MM cells. Finally, we show an additive effect of arsenic trioxide on apoptosis when used in combination with ZOL. Conclusions: Our in vitro data suggest that the use of ZOL at appropriate doses could be explored clinically in bortezomib-resistant MM patients and combined with arsenic trioxide to increase its proapoptotic effect.
AB - Objective: Multiple myeloma (MM) cells are extremely resistant to drug-induced apoptosis due to both intrinsic- and bone marrow (BM) microenvironment-dependent drug resistance particularly supported by bone cells. Growing evidence suggest that the osteoclast inhibitor zoledronic acid (ZOL) exerts both indirect and direct anti-tumoral effects, including an in vitro proapoptotic effect on MM cells, although this property has not yet been clearly observed in MM patients. Materials and Methods: In this study, we attempt to better define the cytotoxic effect of ZOL on MM cells in order to identify novel drug combinations able to potentiate its proapoptotic effect. Results: Our data shows that ZOL at concentrations ranging from 10 to 100 μM was able to induce MM cell apoptosis overcoming the prosurvival effect of both stromal cells and osteoclasts and independent of the intrinsic bortezomib resistance of MM cells. Interestingly, we found that the capacity of ZOL to induce apoptosis in bortezomib-resistant cells was associated with a downregulation of the proapoptotic molecule myeloid cell leukemia-1. A transcriptional analysis by microarray was also performed to identify genes specifically modulated by ZOL in bortezomib-resistant MM cells. Finally, we show an additive effect of arsenic trioxide on apoptosis when used in combination with ZOL. Conclusions: Our in vitro data suggest that the use of ZOL at appropriate doses could be explored clinically in bortezomib-resistant MM patients and combined with arsenic trioxide to increase its proapoptotic effect.
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U2 - 10.1016/j.exphem.2010.10.005
DO - 10.1016/j.exphem.2010.10.005
M3 - Article
C2 - 20977926
AN - SCOPUS:78650209271
SN - 0301-472X
VL - 39
SP - 55
EP - 65
JO - Experimental Hematology
JF - Experimental Hematology
IS - 1
ER -