靶向多发性骨髓瘤中的磷酸肌醇3激酶和组蛋白去乙酰化酶

Targeting phosphoinositide 3-kinases and histone deacetylases in multiple myeloma.

作者信息

Okabe Seiichi, Tanaka Yuko, Gotoh Akihiko

机构信息

Department of Hematology, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.

出版信息

Exp Hematol Oncol. 2021 Mar 4;10(1):19. doi: 10.1186/s40164-021-00213-6.

BACKGROUND

Multiple myeloma (MM) is a type of hematological malignancy affecting the functions of plasma cells. The treatment of MM patients has changed dramatically with the use of new agents. However, unfortunately, it is still incurable. Therefore, a new approach for treating MM is still needed to improve patient outcomes.

METHODS

Because the histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) pathway is a key signal in cancer cell biology, we investigated whether dual HDAC and PI3K inhibitors could suppress the myeloma cells.

RESULTS

Gene expression of HDACs is high in myeloma cells. CUDC-907, a dual inhibitor of PI3K and HDAC, inhibits HDAC activity. Akt activity and expression of BCL-XL, MCL-1, and NF-κB p65 were reduced by CUDC-907 in a dose-dependent manner. The number of apoptotic and caspase 3/7-positive cells also increased in the myeloma cells. Combined treatment of myeloma cells with carfilzomib and CUDC-907 increased cytotoxicity compared to that observed with each drug alone.

CONCLUSIONS

Data from this study suggested that the administration of CUDC-907 might be a powerful strategy against myeloma cells, to enhance the cytotoxic effects of proteasome inhibitors.

背景

多发性骨髓瘤（MM）是一种影响浆细胞功能的血液系统恶性肿瘤。随着新型药物的使用，MM患者的治疗发生了巨大变化。然而，不幸的是，它仍然无法治愈。因此，仍需要一种新的治疗MM的方法来改善患者的预后。

方法

由于组蛋白去乙酰化酶（HDAC）和磷脂酰肌醇3-激酶（PI3K）信号通路是癌细胞生物学中的关键信号，我们研究了HDAC和PI3K双重抑制剂是否能抑制骨髓瘤细胞。

结果

骨髓瘤细胞中HDACs的基因表达较高。PI3K和HDAC双重抑制剂CUDC-907可抑制HDAC活性。CUDC-907能以剂量依赖的方式降低Akt活性以及BCL-XL、MCL-1和NF-κB p65的表达。骨髓瘤细胞中凋亡细胞和caspase 3/7阳性细胞的数量也增加。与单独使用每种药物相比，卡非佐米和CUDC-907联合治疗骨髓瘤细胞可增加细胞毒性。