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.

journal_name

Oncol Rep

journal_title

Oncology reports

authors

Pillozzi S,Bernini A,Spiga O,Lelli B,Petroni G,Bracci L,Niccolai N,Arcangeli A

doi

10.3892/or.2018.6808

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

312-324

issue

1

eissn

1021-335X

issn

1791-2431

journal_volume

41

pub_type

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