Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation.
Multiple myeloma is characterized by the accumulation of clonal malignant plasma cells in the bone marrow, which stimulates bone destruction by osteoclasts and reduces bone formation by osteoblasts. In turn, the changed bone microenvironment sustains survival of myeloma cells. Therefore, a challenge for treating multiple myeloma is discovering drugs targeting not only myeloma cells but also osteoclasts and osteoblasts. Because resveratrol (trans-3,4',5-trihydroxystilbene) is reported to display antitumor activities on a variety of human cancer cells, we investigated the effects of this natural compound on myeloma and bone cells. We found that resveratrol reduces dose-dependently the growth of myeloma cell lines (RPMI 8226 and OPM-2) by a mechanism involving cell apoptosis. In cultures of human primary monocytes, resveratrol inhibits dose-dependently receptor activator of nuclear factor-kappaB (NF-kappaB) ligand-induced formation of tartrate-resistant acid phosphatase (TRACP)-positive multinucleated cells, TRACP activity in the medium, up-regulation of cathepsin K gene expression, and bone resorption. These inhibitions are associated with a down-regulation of RANK expression at both mRNA and cell surface protein levels and a decrease of NFATc1 stimulation and NF-kappaB nuclear translocation, whereas the gene expression of c-fms, CD14, and CD11a is up-regulated. Finally, resveratrol promotes dose-dependently the expression of osteoblast markers like osteocalcin and osteopontin in human bone marrow mesenchymal stem cells (hMSC-TERT) and stimulates their response to 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. Moreover, resveratrol up-regulates dose-dependently the expression of 1,25(OH)2D3 nuclear receptor. Taken together, these results suggest that resveratrol or its derivatives deserve attention as potential drugs for treating multiple myeloma.
Boissy
Patrice
P
Clinical Research Unit and Division of Hematology, Vejle Hospital, Vejle, Southern Denmark University Network, Denmark. patboi@vgs.vejleamt.dk
Andersen
Thomas L
TL
Abdallah
Basem M
BM
Kassem
Moustapha
M
Plesner
Torben
T
Delaissé
Jean-Marie
JM
D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053495:Osteopontin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D000077185:Resveratrol; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018167:Receptors, Calcitriol; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D013267:Stilbenes; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D015675:Osteocalcin; D053495:Osteopontin; D016173:Macrophage Colony-Stimulating Factor; D002117:Calcitriol; D000077185:Resveratrol