Metabolic Mechanisms and a Rational Combinational Application of Carboxyamidotriazole in Fighting Pancreatic Cancer Progression after Chemotherapy

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.

Selected 5-amino-1-aryl-1H-1,2,3-triazole scaffolds as promising antiproliferative agents

“…On the contrary, the selective influence of [1,2,3] activity below moderate (mostly active on NCI-H522 Lung Cancer cell line) ( Table 1). In general, it can be concluded that the replacement of the amide moiety at position 4 of 1h-1,2,3-triazole leads to a decrease or loss of its anticancer activity.…”

“…1) capable of binding to and inhibiting of the non-voltage-operated Ca 2+ channels and blocking cellular Ca 2+ influx and release, cause a disruption of calcium channel-mediated signal transduction and inhibition of vascular endothelial growth factor signalling, endothelial proliferation, and angiogenesis [1]. This agent is also widely used in cancer therapy [2][3][4]. Carboxyamidotriazole inhibits growth of H345 small cell lung cancer cells via VEGF-dependent pathway.…”

“…The antineoplastic action of carboxyamidotriazole in combination with other drugs was studied . The combination of carboxyamidotriazole and glycolysis inhibitor 2-deoxyglucose inhibited the pancreatic cancer progression [3]. Chen et al (2017) reported that the combination of sorafenib and carboxyamidotriazole inhibited the proliferation of nonsmall cell lung cancer cells of A549 and NCI-H1975 lines in vitro, and Lewis lung carcinoma bearing mice [4].…”

“…2). Moreover, the amino-fused 1,2,3-triazole: 5-oxo-4,5,6,7,8,9-hexahydrobenzo [4,5]thieno [3,2-e] [1,2,3]triazolo [1,5-a]pyrimidine-3-carboxamide possessed a selective action towards melanoma SK-MEL-5 cells (GP = -31,50%) [8] (Fig. 2).…”

“…2). Other scaffolds such as 4-(1h-indole-3-carbonyl)-5-amino-1h-1,2,3-triazoles, 4-arylsulfonyl-5-amine-1h-1,2,3-triazoles, [1,2,3]triazolo [1,5-a]quinazolines demonstrated moderate or low antiproliferative activity [7,8] (Fig. 2).…”