The A2badenosine receptor antagonist PSB-603 promotes oxidative phosphorylation and ROS production in colorectal cancer cells via adenosine receptor-independent mechanism.
Adenosine is a multifaceted regulator of tumor progression. It modulates immune cell activity as well as acting directly on tumor cells. The A2badenosine 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.



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.



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.
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Christina
C
Mølck
Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia.
James
J
Ryall
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Laura M
LM
Failla
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Janine L
JL
Coates
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; INSERM, U1191, F-34000 Montpellier, France; Universités de Montpellier, F-34000 Montpellier, France.
Jean-Marc
JM
Pascussi
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.
Joan K
JK
Heath
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Gregory
G
Stewart
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: frederic.hollande@unimelb.edu.au.
Frédéric
F
Hollande
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D014970:Xanthines / Q000494:pharmacology*
D058917:Adenosine A2 Receptor Antagonists; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C000592275:PSB603; D017382:Reactive Oxygen Species; D043704:Receptor, Adenosine A2B; D013449:Sulfonamides; D014970:Xanthines; D000077150:Oxaliplatin; D000242:Cyclic AMP; D005472:Fluorouracil
Cellular redox state; Chemotherapy; MTT; Off-target effect; PSB603; Reactive oxygen species