Abstract
Background: Acute myeloid leukemia (AML) is a malignant heterogeneous group of hematological diseases that originates from a hematopoietic progenitor with altered maturation capacity. Recently, considerable advances have been made in the development of targeted therapies for distinct molecularly defined subtypes. Although many AML patients initially respond to current treatment, the majority of them relapse. Therefore, new targeted therapies are needed to overcome drug resistance and improve treatment effectiveness. CXCR4 is a chemokine receptor that is expressed in over 20 cancer types, both hematologic cancers and solid tumors. CXCR4 receptor and its ligand CXCL12 are key mediators of the interactions between AML cells and the bone marrow (BM) microenvironment. Moreover, CXCR4 is highly expressed in around 50% of AML patients. Thus, we have generated a nanoparticle (T22-PE24-H6) that selectively delivers the exotoxin A from Pseudomonas aeruginosa to CXCR4+ leukemic cells. Aims: To assess the selectivity of T22-PE24-H6 cytotoxicity in CXCR4+ AML cell lines as well as in BM samples from AML patients. In addition, we evaluated the antineoplastic effect of the nanoparticle in a CXCR4+ AML disseminated mouse model. Methods: OCI-AML-3, MONO-MAC-6 and HEL cell lines were characterized for CXCR4 expression using flow cytometry and immunohistochemistry (IHC). The in vitro antineoplastic effect of T22-PE24-H6 was determined by cell viability assays. Competition assays with the CXCR4 antagonist AMD3100 were performed to demonstrate the CXCR4-dependent cytotoxicity of the nanoparticle. In vivo effect was assessed in NSG mice intravenously injected with 1x106 luminescent MONO-MAC-6 cells. Animals were treated with 5 μg T22-PE24-H6 or Buffer (166 mM NaCO3H pH 8) daily for 10 doses. Bioluminescence signal (BLI) was monitored to quantitatively measure and evaluate in vivo disease progression. Animal tissue samples were collected after mice euthanasia and used to analyze AML dissemination and toxicity. CXCR4 expression levels and T22-PE24-H6 effect were also determined in BM samples from 10 newly-diagnosed AML patients. Results: T22-PE24-H6 nanoparticle demonstrated a potent in vitro anticancer effect in MONO-MAC-6 cell line. The specific cytotoxic activity of the nanoparticle was CXCR4 dependent as demonstrated by performing competition assays with AMD3100. Furthermore, T22-PE24-H6 intravenous administrations showed significant BLI reduction in a CXCR4+ AML disseminated mouse model compared to buffer-treated mice. In addition, no differences between groups in mouse body weight, biochemical parameters or histopathological changes in normal tissues were detected. Finally, T22-PE24-H6 causes a significant cell viability reduction in AML patient samples with high CXCR4 expression. In contrast, the nanoparticle has no effect in AML patient samples with low expression of CXCR4. Summary/Conclusion: T22-PE24-H6 selectively kills AML cell lines and BM samples from AML patients with CXCR4 overexpression. The nanoparticle also induces a high antineoplastic effect in a CXCR4+ AML disseminated mouse model without detectable systemic toxicity. These data strongly support that T22-PE24-H6 may obtain therapeutic benefit for AML patients with high CXCR4 expression.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
