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Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Authors :
Ali Vaziri-Gohar
Jonathan J. Hue
Hallie G. Graor
Ata Abbas
Mehrdad Zarei
Omid Hajihassani
George Titomihelakis
John Feczko
Moeez Rathore
Rui Wang
Mahsa Zarei
Maryam Goudarzi
Renliang Zhang
Belinda Willard
Li Zhang
Gi-Ming Wang
Curtis Tatsuoka
Joseph M. Salvino
Ilya Bederman
Henri Brunengraber
Costas A. Lyssiotis
Jonathan R. Brody
Jordan M. Winter
Publication Year :
2022
Publisher :
Cold Spring Harbor Laboratory, 2022.

Abstract

SummaryPancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........9ea8b1ecbe72f15cd57d41e641d9490f
Full Text :
https://doi.org/10.1101/2022.04.29.490090