Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
Int J Hematol. 2011 Apr;93(4):482-493. doi: 10.1007/s12185-011-0821-z. Epub 2011 Mar 31.
The purpose of this study was to investigate the antitumor effects and drug interactions of the proteasome inhibitor Bortezomib against high-risk myelodysplastic syndrome (MDS) cells in vitro and in vivo. The high-risk MDS-derived MUTZ-1 cell line and bone marrow mononuclear cells from primary high-risk MDS patients were used to examine antitumor activity and drug interactions for Bortezomib. Apoptotic proteins, including caspase and Bcl-2 family members, as well as the protein FLIP, were studied. Phosphoinositide 3-kinase (PI3K)/Akt and MAPK signaling pathways were also examined. The PI3K inhibitor LY294002 was used to examine the involvement of the PI3K/Akt signaling pathway in the induction of apoptosis. Cytarabine (AraC) and daunorubicin (DNR) were used to test for synergistic effects between Bortezomib and chemotherapeutic agents. SCID mice xenografted with MUTZ-1 cells were used for in vivo study. We found that Bortezomib could induce growth arrest and apoptosis in high-risk MDS cells in vitro and in vivo. The mechanisms were related to decreased activation of the PI3K/Akt survival signaling pathway, but not the MAPK pathway, and involved inhibition of the NF-κB activity and downregulation of the Bcl-2/Bax and FLIPL/FLIPS ratios, triggering the activation of caspase cascades. This phenomenon was inhibited by the PI3K inhibitor LY294002. Bortezomib also acted synergistically with the chemotherapeutic agents AraC and DNR, which are associated with the inhibition of NF-κB activity. Our results demonstrate that Bortezomib can induce growth arrest and apoptosis of high-risk MDS cells and had a synergistic effect with two chemotherapeutic agents. Our findings provide new insights for the treatment of high-risk MDS, using either Bortezomib alone, or in combination with conventional antineoplastic agents.
本研究旨在探讨蛋白酶体抑制剂硼替佐米（Bortezomib）在体外和体内对高危骨髓增生异常综合征（MDS）细胞的抗肿瘤作用和药物相互作用。使用高危 MDS 衍生的 MUTZ-1 细胞系和来自原发性高危 MDS 患者的骨髓单个核细胞来检测硼替佐米的抗肿瘤活性和药物相互作用。研究了凋亡蛋白，包括半胱天冬酶和 Bcl-2 家族成员，以及蛋白 FLIP。还研究了磷酸肌醇 3-激酶（PI3K）/Akt 和 MAPK 信号通路。使用 PI3K 抑制剂 LY294002 来检测 PI3K/Akt 信号通路在诱导凋亡中的参与。使用阿糖胞苷（AraC）和柔红霉素（DNR）来测试硼替佐米与化疗药物之间的协同作用。使用 MUTZ-1 细胞异种移植的 SCID 小鼠进行体内研究。我们发现硼替佐米可以在体外和体内诱导高危 MDS 细胞的生长停滞和凋亡。其机制与降低 PI3K/Akt 存活信号通路的激活有关，但与 MAPK 通路无关，涉及抑制 NF-κB 活性和下调 Bcl-2/Bax 和 FLIPL/FLIPS 比值，触发半胱天冬酶级联的激活。这种现象被 PI3K 抑制剂 LY294002 抑制。硼替佐米还与化疗药物 AraC 和 DNR 协同作用，这与抑制 NF-κB 活性有关。我们的结果表明，硼替佐米可以诱导高危 MDS 细胞的生长停滞和凋亡，并与两种化疗药物具有协同作用。我们的研究结果为使用硼替佐米单独或与传统抗肿瘤药物联合治疗高危 MDS 提供了新的见解。
