Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis

Xiaojuan Yang, Jiuxia Pang, Na Shen, Fei Yan, Lai Chu Wu, Aref Al-Kali, Mark R. Litzow, Yong Peng, Robert J. Lee, Shujun Liu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 Tftargeted 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.

Original languageEnglish (US)
Pages (from-to)36382-36394
Number of pages13
Issue number24
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported in part by National Cancer Institute (Bethesda, MD) grants R01CA149623 (S. Liu), R21CA155915 (S. Liu) and Hormel Institute Foundation (S. Liu).


  • Bortezomib
  • Chronic myeloid leukemia
  • Liposome
  • Nanoparticle


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