Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma.
Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma.
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DOI：
10.1007/s13402-011-0060-6
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发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Nefedova Y
中科院分区：
文献类型：
--
作者：
Chen F;Pisklakova A;Li M;Baz R;Sullivan DM;Nefedova Y
γ-分泌酶抑制剂（GSIs）靶向Notch信号已被认为是治疗包括多发性骨髓瘤（MM）在内的血液系统恶性肿瘤的一种有前景的策略。在这里，我们研究了硼替佐米（一种常用于MM的药物）的细胞毒作用是否可以通过添加GSI来增强。用GSI、硼替佐米或两者联合处理MM细胞。观察MM细胞凋亡、蛋白酶体活性和Notch信号激活情况。在转染Notch-1活性结构域的MM细胞中，也评估了联合用药的效果。使用MM细胞系和从MM患者骨髓中分离的原代MM细胞，我们发现硼替佐米与所研究的一种gsi联合使用具有很强的协同作用。接下来，我们研究了这种协同作用的机制，并确定药物联合作用主要取决于所选GSI抑制MM细胞蛋白酶体活性的能力。我们的研究表明，选定的抑制蛋白酶体活性的gsi可以成功地与硼替佐米联合使用，增强其抗mm的作用。
Targeting of Notch signaling with γ-secretase inhibitors (GSIs) has been considered a promising strategy for the treatment of hematological malignancies including multiple myeloma (MM). Here we investigated whether the cytotoxic effect of bortezomib, an agent commonly used in MM, could be enhanced by the addition of a GSI. MM cells were treated with GSI, bortezomib or the combination thereof. Apoptosis of MM cells, proteasome activity and Notch signaling activation were determined. The effect of the drug combination was also evaluated in MM cells transfected with the active domain of Notch-1. Using MM cell lines and primary MM cells isolated from the bone marrow of patients with MM we found a strong synergistic effect of bortezomib in combination with one of the GSIs studied. We next investigated the mechanism underlying this synergistic effect and determined that the effect of the drug combination was mainly dependent on the ability of the selected GSI to inhibit proteasome activity in MM cells. Our study demonstrates that selected GSIs that inhibit proteasome activity may be successfully used in combination with bortezomib enhancing its anti-MM effect.
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影响因子：
20.3
作者：
Jundt, F;Pröbsting, KS;Dörken, B
通讯作者：
Dörken, B
影响因子：
20.3
作者：
Nefedova, Yulia;Sullivan, Daniel M.;Gabrilovich, Dmitry I.
通讯作者：
Gabrilovich, Dmitry I.
影响因子：
3.3
作者：
Skrtic, Anita;Korac, Petra;Dominis, Mara
通讯作者：
Dominis, Mara
影响因子：
5.2
作者：
Monticone, Massimiliano;Biollo, Emanuela;Castagnola, Patrizio
通讯作者：
Castagnola, Patrizio
DOI：
10.1186/bcr2347
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Han J;Ma I;Hendzel MJ;Allalunis-Turner J
通讯作者：
Allalunis-Turner J