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Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis
Author(s) -
Yang Xiao,
Jiuxia Pang,
Na Shen,
Fei Yan,
Lai-Chu Wu,
Aref AlKali,
Mark R. Litzow,
Yong Peng,
Robert J. Lee,
Shujun Liu
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.8871
Subject(s) - medicine , cancer research , breakpoint cluster region , myeloid leukemia , receptor
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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