Centro de Investigación del Cáncer, IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain.
Ann Hematol. 2012 Feb;91(2):257-69. doi: 10.1007/s00277-011-1287-z. Epub 2011 Jul 1.
Despite the advantage observed with novel drugs such as bortezomib, thalidomide, or lenalidomide, multiple myeloma (MM) remains incurable and there is a clear need for new drugs or combinations based on the pathogenetic mechanism of MM. One of the proposed mechanisms in MM pathogenesis is the involvement of kinase molecules in the growth and survival of myelomatous cells. In this study, we have explored the optimal combination for dasatinib, a tyrosine kinase inhibitor, in MM cells. A clear synergistic effect was observed with the triple combination of dasatinib with bortezomib and dexamethasone which was evident even in the presence of bone marrow microenvironment. Experiments performed on freshly isolated patients' cells also demonstrated potentiation of response in the triple as compared with the agents alone or in double combinations. Gene expression profiling experiments provided some clues on the transcriptional rationale underlying this potentiation, as the triple combination led to significant deregulation of genes involved in cell death, cell growth, proliferation, DNA replication, repair and recombination, and cell-cell signaling. Some of these results were further confirmed by apoptosis and cell cycle experiments and also by Western blot and PCR. These data provide the rationale for the use of this novel combination in MM patients.
尽管新型药物如硼替佐米、沙利度胺或来那度胺具有优势，但多发性骨髓瘤（MM）仍然无法治愈，显然需要基于 MM 的发病机制的新药或联合用药。MM 发病机制中的一个提出的机制是激酶分子参与骨髓瘤细胞的生长和存活。在这项研究中，我们探索了达沙替尼（一种酪氨酸激酶抑制剂）与硼替佐米和地塞米松联合应用的最佳组合。达沙替尼与硼替佐米和地塞米松的三联组合具有明显的协同作用，即使在骨髓微环境存在的情况下也是如此。对新分离的患者细胞进行的实验也表明，三联组合与单独使用或双重组合相比，反应增强。基因表达谱实验为这种增效作用的转录基础提供了一些线索，因为三联组合导致参与细胞死亡、细胞生长、增殖、DNA 复制、修复和重组以及细胞间信号传导的基因显著失调。其中一些结果通过凋亡和细胞周期实验以及 Western blot 和 PCR 进一步得到证实。这些数据为在 MM 患者中使用这种新组合提供了依据。
