The A2b adenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism

Christina Mølck, James Ryall, Laura M Failla, Janine L Coates, Jean Marc Pascussi, Joan K. Heath, Gregory Stewart, Frédéric Hollande

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Purpose Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A2b adenosine receptor (A2b-AR) is thought to be an important mediator of these effects. In this study we sought to analyze the contribution of the A2b-AR to the behavior of colorectal cancer cells. Principal results The A2b-AR antagonist PSB-603 changed cellular redox state without affecting cellular viability. Quantification of cellular bioenergetics demonstrated that PSB-603 increased basal oxygen consumption rates, indicative of enhanced mitochondrial oxidative phosphorylation. Unexpectedly, pharmacological and genetic approaches to antagonize AR-related signalling of PSB-603 did not abolish the response, suggesting that it was AR-independent. PSB-603 also induced acute increases in reactive oxygen species, and PSB-603 synergized with chemotherapy treatment to increase colorectal cancer cell death, consistent with the known link between cellular metabolism and chemotherapy response. Major conclusions PSB-603 alters cellular metabolism in colorectal cancer cells and increases their sensitivity to chemotherapy. Although requiring more mechanistic insight into its A2b-AR-independent activity, our results show that PSB-603 may have clinical value as an anti-colorectal cancer therapeutic.

Original languageEnglish
Pages (from-to)135-143
Number of pages9
JournalCancer Letters
Volume383
Issue number1
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • Cellular redox state
  • Chemotherapy
  • MTT
  • Off-target effect
  • PSB603
  • Reactive oxygen species

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