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.

Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant

“…1f ). Our results are consistent with the report by Yang et al 27 that Sp1, in an EMSA assay, can bind to the promoter of WT- BCR-ABL fusion gene and that silencing Sp1 can diminish expression of WT- BCR-ABL . These findings may lay the foundation for endowing Sp1 an attractive therapeutic target in CML patients bearing T315I-BCR-ABL .…”

“…Synergistic effect between niclosamide and imatinib in the abilities of inducing reduced proliferation and apoptotic cell death was, indeed, noted in imatinib-resistant and -sensitive CML cells. Given that Sp1 expression can be suppressed by the clinically available drug Bortezomib, an ubiquitin-proteasome inhibitor, in tumor cells 27 , our findings imply a rationale for a clinical trial of combination between imatinib and Bortezomib.…”

“…The expression of BCR-ABL oncogene is positively regulated by transcription factor Sp1 27 . To investigate whether the decrease of BCR-ABL levels by niclosamide was mediated by Sp1, we assessed the effect of niclosamide on the expression levels of Sp1 by Western blotting analysis.…”

“…In the context of BCR-ABL oncogene, its transcription is positively regulated by transcription factor Sp1. Silencing Sp1 can diminish BCR-ABL expression and abolish its downstream signaling 27 . However, whether Sp1 regulates T315I- BCR-ABL mutant oncogene remains elusive.…”

Nanocarriers as Magic Bullets in the Treatment of Leukemia

“…In this context, Liu et al encapsulated homoharringtonine, a drug for patients resistant to TKIs, into PEGylated liposome, and they demonstrated comparable safety and lower toxicity as opposed to the bare drug [137]. In another study, loading bortezomib into liposome conjugated to transferrin significantly targeted CML resistant cells to doxorubicin and made them more sensitive to this agent [138]. Jyotsana et al designed a liposome loaded with siRNA against BCR-ABL1 and claimed that this system could decrease the disease burden in the mouse model of CML [139].…”