Oncotarget

Research Papers:

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 and Shujun Liu _

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Oncotarget. 2016; 7:36382-36394. https://doi.org/10.18632/oncotarget.8871

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Abstract

Xiaojuan Yang1,2,4,*, Jiuxia Pang1,*, Na Shen1, Fei Yan1, Lai-Chu Wu2, Aref Al-Kali4, Mark R. Litzow4, Yong Peng5, Robert J. Lee3, Shujun Liu1

1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA

2Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA

3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA

4Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA

5Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China

*These authors have contributed equally to this work

Correspondence to:

Shujun Liu, email: [email protected]

Robert J. Lee, email: [email protected]

Yong Peng, email: [email protected]

Keywords: BCR/ABL, chronic myeloid leukemia, bortezomib, nanoparticle, liposome

Received: February 03, 2016     Accepted: March 31, 2016     Published: April 20, 2016

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 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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