Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341
Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341
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DOI：
10.1182/blood-2002-08-2543
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发表时间：
2003-02-15
期刊：
影响因子：
20.3
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Hideshima, T;Mitsiades, C;Anderson, KC
我们最近发现，蛋白酶体抑制剂PS-341诱导耐药多发性骨髓瘤（MM）细胞凋亡，抑制骨髓微环境中MM细胞的结合，并抑制介导MM细胞生长，存活，耐药性和体外迁移的细胞因子。PS-341还可抑制SCID小鼠模型中的人MM细胞生长和骨髓瘤存活。重要的是，PS-341在难治性复发性MM患者中取得了显著的临床反应。我们在此证实了PS-341通过诱导p53和MDM 2蛋白表达、诱导p53蛋白磷酸化（Ser 15）、激活c-Jun氨基末端激酶（JNK）、半胱天冬酶-8和半胱天冬酶-3介导抗MM活性的分子机制。以及切割DNA蛋白激酶催化亚基、ATM和MDM 2。JNK活性的抑制消除了PS-341诱导的MM细胞死亡。这些研究确定了PS-341的分子靶点，并为开发第二代更具靶向的治疗提供了理论基础。(C)2003年，美国血液学会。
We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myelloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and I migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical res. ponses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity a abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies. (C) 2003 by The American Society of Hematology.