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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., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Targeting cancer cell metabolism is a promising strategy against cancer. Here, we confirmed that the anti-cancer drug carboxyamidotriazole (CAI) inhibited mitochondrial respiration in cancer cells for the first time and found a way to enhance its anti-cancer activity by further disturbing the energy metabolism. CAI promoted glucose uptake and lactate production when incubated with cancer cells. The oxidative phosphorylation (OXPHOS) in cancer cells was inhibited by CAI, and the decrease in the activity of the respiratory chain complex I could be one explanation. The anti-cancer effect of CAI was greatly potentiated when being combined with 2-deoxyglucose (2-DG). The cancer cells treated with the combination of CAI and 2-DG were arrested in G2/M phase. The apoptosis and necrosis rates were also increased. In a mouse xenograft model, this combination was well tolerated and retarded the tumor growth. The impairment of cancer cell survival was associated with significant cellular ATP decrease, suggesting that the combination of CAI and 2-DG could be one of the strategies to cause dual inhibition of energy pathways, which might be an effective therapeutic approach for a broad spectrum of tumors., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Carboxyamidotriazole (CAI) is a non-cytotoxic anti-tumor drug, which also shows considerable anti-inflammatory effects in a variety of animal models of inflammation. The exact target and mechanism of CAI were not clearly understood yet. In the present study, we demonstrate that CAI is a non-selective phosphodiesterase (PDE) inhibitor, which provides comprehensive inhibitions of both adenosine 3',5'-cyclic monophosphate specific PDE (cAMP-PDE) and guanosine 3',5'-cyclic monophosphate specific PDE (cGMP-PDE) isolated from rat brain, mouse pulmonary tissue, primary mouse peritoneal macrophages, RAW264.7 cells, Lewis lung carcinoma (LLC) cells and lymphocytic leukemia cells (L1210) with moderate potencies (IC50≈0.5-30μM). The comprehensive elimination of PDE activities in living LLC cells by CAI results in accumulation of intracellular cAMP and cGMP, which can be visualized by fluorescence resonance energy transfer (FRET)-based cyclic nucleotide sensors. The stimulation by 30μM CAI yielded ~1.5-fold greater cGMP responses compared with 10μM sildenafil citrate, whereas the influence of 30μM CAI on cAMP levels was similar as that of 100μM 3-isobutyl-1-methylxanthine (IBMX). The non-selective inhibitory effect of CAI on cAMP-PDE and cGMP-PDE increases the likelihood for CAI to affect the balance between the levels of intracellular cyclic nucleotides cAMP and cGMP, then a variety of cellular signaling pathways that regulate cell functions and even related disease processes. When examining the widely proven anti-tumor and anti-inflammatory activities of CAI, it is important to affirm its comprehensive inhibitory effect on PDEs, which makes it superior to some selective PDE inhibitors in a way., (Copyright © 2014. Published by Elsevier B.V.)