Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis.
Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis.
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DOI：
10.18632/oncotarget.8871
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Yang X;Pang J;Shen N;Yan F;Wu LC;Al-Kali A;Litzow MR;Peng Y;Lee RJ;Liu S
The abundance of the BCR/ABL protein critically contributes to CML pathogenesis and drug resistance. However, understanding of molecular mechanisms underlying BCR/ABL gene regulation remains incomplete. While BCR/ABL kinase inhibitors have shown unprecedented efficacy in the clinic, most patients relapse. In this study, we demonstrated that the Sp1 oncogene functions as a positive regulator for BCR/ABL expression. Inactivation of Sp1 by genetic and pharmacological approaches abrogated BCR/ABL expression, leading to suppression of BCR/ABL kinase signaling and CML cell proliferation. Because of potential adverse side effects of bortezomib (BORT) in imatinib-refractory CML patients, we designed a transferrin (Tf)-targeted liposomal formulation (Tf-L-BORT) for BORT delivery. Cellular uptake assays showed that BORT was efficiently delivered into K562 cells, with the highest efficacy obtained in Tf-targeted group. After administered into mice, L-BORT exhibited slower clearance with less toxicity compared to free BORT. Furthermore, L-BORT exposure significantly blocked BCR/ABL kinase activities and sensitized CML cell lines, tumor cells and doxorubicin (DOX) resistant cells to DOX. This occurred through the more pronounced inhibition of BCR/ABL activity by L-BORT and DOX. Collectively, these findings highlight the therapeutic relevance of disrupting BCR/ABL protein expression and strongly support the utilization of L-BORT alone or in combination with DOX to treat CML patients with overexpressing BCR/ABL.
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DOI：
10.1016/j.clml.2011.06.004
发表时间：
2011-08
期刊：
Clinical lymphoma, myeloma & leukemia
影响因子：
--
作者：
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通讯作者：
Cortes J
影响因子：
6.4
作者：
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通讯作者：
Ueda, Takanori
影响因子：
11.4
作者：
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通讯作者：
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影响因子：
11.4
作者：
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通讯作者：
McKenna, SL
影响因子：
158.5
作者：
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通讯作者：
Holmes, H