Boissy Patrice, Andersen Thomas L, Abdallah Basem M, Kassem Moustapha, Plesner Torben, Delaissé Jean-Marie
Clinical Research Unit and Division of Hematology, Vejle Hospital, Vejle, Southern Denmark University Network, Denmark.
Cancer Res. 2005 Nov 1;65(21):9943-52. doi: 10.1158/0008-5472.CAN-05-0651.
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.
多发性骨髓瘤的特征是骨髓中克隆性恶性浆细胞的积累，这会刺激破骨细胞导致骨破坏，并减少成骨细胞的骨形成。反过来，改变的骨微环境维持了骨髓瘤细胞的存活。因此，治疗多发性骨髓瘤的一个挑战是发现不仅靶向骨髓瘤细胞，而且靶向破骨细胞和成骨细胞的药物。由于白藜芦醇（反式 - 3,4',5 - 三羟基芪）据报道对多种人类癌细胞具有抗肿瘤活性，我们研究了这种天然化合物对骨髓瘤细胞和骨细胞的影响。我们发现白藜芦醇通过涉及细胞凋亡的机制剂量依赖性地降低骨髓瘤细胞系（RPMI 8226和OPM - 2）的生长。在人原代单核细胞培养物中，白藜芦醇剂量依赖性地抑制核因子 - κB（NF - κB）配体诱导的抗酒石酸酸性磷酸酶（TRACP）阳性多核细胞的形成、培养基中的TRACP活性、组织蛋白酶K基因表达的上调以及骨吸收。这些抑制作用与RANK在mRNA和细胞表面蛋白水平的下调以及NFATc1刺激和NF - κB核转位的减少相关，而c - fms、CD14和CD11a的基因表达上调。最后，白藜芦醇剂量依赖性地促进人骨髓间充质干细胞（hMSC - TERT）中骨钙素和骨桥蛋白等成骨细胞标志物的表达，并刺激它们对1,25(OH)2维生素D3 [1,25(OH)2D3]的反应。此外，白藜芦醇剂量依赖性地上调1,25(OH)2D3核受体的表达。综上所述，这些结果表明白藜芦醇或其衍生物作为治疗多发性骨髓瘤的潜在药物值得关注。
