Department of Medical Oncology, Dana-Farber Cancer Institute, M551, 450 Brookline Avenue, Boston, MA 02115, USA.
Curr Pharm Des. 2013;19(4):734-44.
Multiple Myeloma (MM) is a common hematologic malignancy of plasma cells representing an excellent model of epigenomics dysregulation in human disease. Importantly, these findings, in addition to providing a better understanding of the underlying molecular changes leading to this malignance, furnish the basis for an innovative therapeutic approach. Histone deacetylase inhibitors (HDACIs), including Vorinostat and Panobinostat, represent a novel class of drugs targeting enzymes involved in epigenetic regulation of gene expression, which have been evaluated also for the treatment of multiple myeloma. Although the clinical role in this setting is evolving and their precise utility remains to be determined, to date that single-agent anti-MM activity is modest. More importantly, HDACIs appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, mainly proteasome inhibitors including bortezomib. The molecular basis underlying this synergism seems to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment. Here we review molecular events underling antitumor effects of HDACIs and the most recent results of clinical trials in relapsed and refractory MM.
多发性骨髓瘤（MM）是一种常见的浆细胞血液恶性肿瘤，是人类疾病中表观基因组失调的一个极好模型。重要的是，除了提供对导致这种恶性肿瘤的潜在分子变化的更好理解之外，这些发现还为创新的治疗方法提供了基础。组蛋白去乙酰化酶抑制剂（HDACIs），包括伏立诺他和帕比司他，代表了一类针对参与基因表达表观遗传调控的酶的新型药物，这些药物也已被评估用于治疗多发性骨髓瘤。尽管在这种情况下的临床作用正在发展，其确切用途仍有待确定，但迄今为止，单一药物抗 MM 活性是适度的。更重要的是，HDACIs 似乎在体外和体内与其他抗 MM 药物联合使用时具有协同作用，主要是蛋白酶体抑制剂，包括硼替佐米。这种协同作用的分子基础似乎是多因素的，涉及到蛋白降解的干扰以及骨髓瘤细胞与微环境的相互作用。在这里，我们回顾了 HDACIs 抗肿瘤作用的分子事件以及复发性和难治性 MM 的最新临床试验结果。
