Format

Send to

Choose Destination
Cancer Lett. 2016 Dec 1;383(1):135-143. doi: 10.1016/j.canlet.2016.09.018. Epub 2016 Sep 28.

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

Author information

1
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
2
Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
4
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; INSERM, U1191, F-34000 Montpellier, France; Universités de Montpellier, F-34000 Montpellier, France.
5
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
6
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
7
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: frederic.hollande@unimelb.edu.au.

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.

KEYWORDS:

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

PMID:
27693637
DOI:
10.1016/j.canlet.2016.09.018
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center