A vascular disrupting agent overcomes tumor multidrug resistance by skewing macrophage polarity toward the M1 phenotype

Cancer Lett. 2018 Apr 1:418:239-249. doi: 10.1016/j.canlet.2018.01.016. Epub 2018 Jan 11.

Abstract

Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters is the major obstacle for chemotherapeutic success. Although attempts have been made to circumvent ABC transporter-mediated MDR in past decades, there is still no effective agent in clinic. Here, we identified a vascular disrupting agent, Z-GP-DAVLBH, that significantly inhibited the growth of multidrug-resistant human hepatoma HepG2/ADM and human breast cancer MCF-7/ADR tumor xenografts, although these cells were insensitive to Z-GP-DAVLBH in vitro. Z-GP-DAVLBH increased the secretion of granulocyte-macrophage colony-stimulating factor in tumor tissues and serum of tumor-bearing mice to skew tumor-associated macrophages from the pro-tumor M2 phenotype to the antitumor M1 phenotype, thereby contributing to the induction of HepG2/ADM and MCF-7/ADR cell apoptosis. Our findings shed new light on the underlying mechanisms of VDAs in the treatment of drug-resistant tumors and provide strong evidence that Z-GP-DAVLBH should be a promising agent for overcoming MDR.

Keywords: Granulocyte-macrophage colony-stimulating factor; Multidrug resistance; Tumor-associated macrophages; Vascular disrupting agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Macrophage Activation / drug effects*
  • Macrophages / classification
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenotype
  • THP-1 Cells
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents