Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer

Cancer Lett. 2023 Jun 1:563:216185. doi: 10.1016/j.canlet.2023.216185. Epub 2023 Apr 14.

Abstract

Pancreatic cancer (PC) has a poor prognosis, and current therapeutic strategies are ineffective in advanced diseases. We and others have shown the aberrant expression of CXCR2 and its ligands in PC development and progression. Our objective for this study was to evaluate the therapeutic utility of CXCR2/1 targeting using an small molecule antagonist, SCH-479833, in different PC preclinical murine models (syngeneic or xenogeneic). Our results demonstrate that CXCR2/1 antagonist had both antitumor and anti-metastatic effects in PC. CXCR2/1 antagonist treatment inhibited tumor cell proliferation, migration, angiogenesis, and recruitment of neutrophils, while it increased apoptosis. Treatment with the antagonist enhanced fibrosis, tumor necrosis, and extramedullary hematopoiesis. Together, these findings suggest that selectively targeting CXCR2/1 with small molecule inhibitors is a promising therapeutic approach for inhibiting PC growth, angiogenesis, and metastasis.

Keywords: Angiogenesis; CXCR2 antagonist; Metastasis; Neutrophils; Pancreatic cancer; Tumor growth.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Mice
  • Pancreatic Neoplasms* / drug therapy
  • Receptors, Interleukin-8A / metabolism
  • Receptors, Interleukin-8B / metabolism

Substances

  • Receptors, Interleukin-8B
  • Receptors, Interleukin-8A