Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia

Leuk Res. 2019 Sep:84:106180. doi: 10.1016/j.leukres.2019.106180. Epub 2019 Jul 3.

Abstract

One of the greatest challenges in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. Previously, we demonstrated a novel mechanism whereby AML-induced endothelial cell (EC) activation leads to subsequent leukemia cell adherence, quiescence and chemoresistance, identifying activated ECs as potential mediators of relapse. We now show mechanistically that EC activation induces the secretion of interleukin-8 (IL-8) leading to significant expansion of non-adherent AML cells and resistance to cytarabine (Ara-C). Through crystallography and computational modeling, we identified a pocket within IL-8 responsible for receptor binding, screened for small molecules that fit within this pocket, and blocked IL-8 induced proliferation and chemo-protection of AML cells with a hit compound. Results from this study show a new therapeutic strategy for targeting the sanctuary of an activated leukemia microenvironment.

Keywords: Acute myeloid leukemia; Chemoresistance; Endothelial cell; Interleukin-8; Microenvironment; Vascular niche.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Biomarkers
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cytarabine / pharmacology
  • Drug Resistance, Neoplasm*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Humans
  • Interleukin-8 / antagonists & inhibitors*
  • Interleukin-8 / chemistry
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Models, Molecular
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Interleukin-8
  • Cytarabine