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Metabolic Mechanisms and a Rational Combinational Application of Carboxyamidotriazole in Fighting Pancreatic Cancer Progression after Chemotherapy.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2018 Oct; Vol. 367 (1), pp. 20-27. Date of Electronic Publication: 2018 Jul 12. - Publication Year :
- 2018
-
Abstract
- The anticancer and anti-inflammatory effects of carboxyamidotriazole (CAI) have been demonstrated in several studies, but the underlying mechanisms remain to be elucidated. This study showed that CAI caused metabolic reprogramming of pancreatic cancer cells. The inhibition of mitochondrial oxidative metabolism by CAI led to increased glutamine-dependent reductive carboxylation and enhanced glycolytic metabolism. The presence of environmental substances that affect cellular metabolism, such as glutamine and pyruvate, attenuated the anticancer efficacy of CAI. Based on the action of CAI: 1) when glutamine was removed, the NAD+/NADH ratio was decreased, the synthesis of cellular aspartate was reduced, and autophagy flux was blocked; and 2) when glycolysis was pharmacologically inhibited, the ATP level was significantly decreased, the cell viability was greatly inhibited, and the compensatory rescue effect of glutamine was eliminated. When combined with chemotherapy, cotreatment with CAI and the glycolysis inhibitor 2-deoxyglucose (2-DG) inhibited the pancreatic cancer progression after chemotherapy. As the inhibition of mitochondrial oxidative metabolism can explain several anticancer activities of CAI reported previously, including inhibition of calcium entry and induction of reactive oxygen species, we demonstrate that inhibition of mitochondrial oxidative phosphorylation may be the fundamental mechanism of CAI. The combination of CAI and 2-DG causes energy depletion in cancer cells, eliminating the rescue effect of the metabolic environment. Inhibiting pancreatic cancer progression after chemotherapy is a rational application of this metabolism-disturbing combination strategy.<br /> (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Aspartic Acid metabolism
Cell Line, Tumor
Cell Proliferation drug effects
Cell Respiration drug effects
Deoxyglucose pharmacology
Drug Interactions
Female
Glycolysis drug effects
Humans
Intracellular Space metabolism
Mice
Mice, Inbred BALB C
Mitochondria drug effects
Mitochondria metabolism
Pancreatic Neoplasms drug therapy
Triazoles therapeutic use
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Disease Progression
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Triazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 367
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 30002095
- Full Text :
- https://doi.org/10.1124/jpet.118.249326