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 journalArticle

13 Scopus citations

Abstract

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
JournalOncotarget
Volume7
Issue number24
DOIs
StatePublished - 2016

Keywords

  • BCR/ABL
  • Bortezomib
  • Chronic myeloid leukemia
  • Liposome
  • Nanoparticle

ASJC Scopus subject areas

  • Oncology

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    Yang, X., Pang, J., Shen, N., Yan, F., Wu, L. C., Al-Kali, A., Litzow, M. R., Peng, Y., Lee, R. J., & Liu, S. (2016). Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis. Oncotarget, 7(24), 36382-36394. https://doi.org/10.18632/oncotarget.8871