title: Liposomal bortezomib is active against chronic myeloid leukemia by disrupting the Sp1-BCR/ABL axis.
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.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.|Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA.|Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Jiuxia
authors.initials: J
authors.lastname: Pang
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Shen
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Aref
authors.initials: A
authors.lastname: Al-Kali
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000069286:Bortezomib / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051562:Proto-Oncogene Proteins c-bcr; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D000069286:Bortezomib; D004317:Doxorubicin; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr
keywords: BCR/ABL; bortezomib; chronic myeloid leukemia; liposome; nanoparticle