Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition

PLoS One. 2017 May 10;12(5):e0177305. doi: 10.1371/journal.pone.0177305. eCollection 2017.

Abstract

We tested the hypotheses that hypoxic stimulation enhances growth potentials of canine lymphoma cells by activating hypoxia-inducible factor 1α (HIF-1α), and that the hypoxia-activated prodrug (TH-302) inhibits growth potentials in the cells. We investigated how hypoxic culture affects the growth rate, chemoresistance, and invasiveness of canine lymphoma cells and doxorubicin (DOX)-resistant lymphoma cells, and influences of TH-302 on survival rate of the cells under hypoxic conditions. Our results demonstrated that hypoxic culture upregulated the expression of HIF-1α and its target genes, including ATP-binding cassette transporter B1 (ABCB1), ATP-binding cassette transporter G2 (ABCG2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and survivin, and enhanced the growth rate, DOX resistance, and invasiveness of the cells. Additionally, TH-302 decreased the survival rate of the cells under hypoxic condition. Our studies suggest that hypoxic stimulation may advance the tumorigenicity of canine lymphoma cells, favoring malignant transformation. Therefore, the data presented may contribute to the development of TH-302-based hypoxia-targeting therapies for canine lymphoma.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Survival / drug effects*
  • Dogs
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hypoxia / drug therapy
  • Hypoxia / genetics
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Lymphoma / drug therapy*
  • Lymphoma / genetics
  • Lymphoma / pathology
  • Nitroimidazoles / pharmacology*
  • Phosphoramide Mustards / pharmacology*
  • Platelet-Derived Growth Factor / genetics
  • Prodrugs / pharmacology*
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitroimidazoles
  • Phosphoramide Mustards
  • Platelet-Derived Growth Factor
  • Prodrugs
  • TH 302
  • Vascular Endothelial Growth Factor A

Grants and funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers 25292180, 15K14872, and 17H03926). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.