Peptides and small molecules blocking the CXCR4/CXCL12 axis overcome bone marrow‑induced chemoresistance in acute leukemias

Abstract

Notable advances in treatment have been made and increases in the cure rates of pediatric leukemia have been achieved. However, the majority of children with relapsed disease are not expected to survive, with chemotherapy resistance acting as the principal cause of treatment failure. Interaction between leukemic cells and the bone marrow microenvironment is the primary cause of relapse. It was identified that a multi-protein membrane complex, formed by potassium voltage-gated channel subfamily H member 2 (hERG1) channels, the β1 integrin subunit and the stromal cell-derived factor 12 (CXCL12) receptor, C-X-C chemokine receptor type 4 (CXCR4), exerts a role in mesenchymal stromal cell (MSC)-mediated chemoresistance in pediatric leukemias. hERG1 blockade was able to overcome chemoresistance in vitro and in vivo. As an alternative strategy to overcome chemoresistance, the present study evaluated the effects of novel tools targeting the CXCR4/CXCL12 axis. The analysis of CXCL12 structural dynamics was used for the selection of a peptide (4-1-17) and a small molecule (8673), which interact with a transient hot spot, identified by a dynamic drug design approach. The present findings indicated that peptide 4-1-17 and small molecule 8673 inhibited leukemia cell proliferation and induced a pro-apoptotic effect, which was not reduced by the presence of MSCs. The combined treatment with 4-1-17 and 8673 had a stronger pro-apoptotic effect, particularly on cells cultured on MSCs in normoxic and hypoxic conditions, and was able to overcome MSC-induced resistance to cytarabine. Overall, the targeting of CXCL12 and the ensuing inhibition of the CXCR4/CXCL12 axis may be proposed as an alternative strategy to overcome chemoresistance in leukemia.type 4/stromal cell-derived factor 12 axis, dynamic drug design, protein-protein interaction disruptors, potassium voltage-gated channel subfamily H member 2 channels, bone marrow stromal cells

Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K

“…no. ab112130; Abcam, Cambridge, UK) was used to detect the activity of caspases 1-9, as previously described 51 .…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…Of note, NFκB enhanced generation of Treg, suppressing the antitumor immune response in a Notch3-dependent T-ALL mouse model [108]. In AML, the activation of CXCR4 is critical for the migration and retention of leukemia cells within the BM, for extramedullary metastasis, chemotherapy resistance [109], and for the maintenance of minimal residual disease (MRD) [110]. Conversely, the inhibition of CXCR4 activity with motixafortide (BL-8040) in phase II clinical trials for relapsed or refractory T-ALL, lymphoblastic lymphoma, and AML induces the apoptosis of AML blasts [111].…”

Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity

“…Many studies have been concerned with the design, synthesis, extraction, and evaluation of the effectiveness of such molecules. In recent years, peptide therapy has become one of the promise candidates for drug development in cancer treatment and other diseases [24,25,26,27,28,29,30,31,32]. Jolene L. Lau and Michael K. Dunn said that peptides represent one of the greatest areas of pharmaceutical development, particularly for tumor treatment, metabolic disease, and cardiovascular disease [33].…”