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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.)

Lung cancer is currently the leading cause of cancer-related deaths worldwide. In this study, we investigated the combination of carboxyamidotriazole (CAI) and sorafenib in non-small cell lung cancer (NSCLC) in vitro and in vivo to test whether CAI enhances the antitumor effects of sorafenib and reduces its side effects. The combination index (CI) showed that coadministration of CAI and sorafenib synergistically inhibited the proliferation of NSCLC cells (Lewis lung carcinoma, A549, and NCI-H1975 cells). Cell death as a result of the combination treatment was attributed to apoptosis, which was accompanied by activation of caspase-3 and poly(ADP-ribose) polymerase. In addition, combination therapy induced the accumulation of mitochondrial-associated reactive oxygen species, as well as depolarization of mitochondrial and reduced NANOG (homeobox protein NANOG) mRNA and protein expression. Basic fibroblast growth factor, a stimulator of NANOG, was applied to identify the possible mechanism. The addition of basic fibroblast growth factor followed by combined treatment may stimulate NANOG expression and synchronously rescue the accumulation of reactive oxygen species. C57BL/6J mice bearing Lewis lung carcinoma were randomized to receive vehicle (polyethylene glycol 400), CAI (30 mg/kg), low-dose sorafenib (SFB-L; 10 mg/kg), high-dose sorafenib (SFB-H; 30 mg/kg), or a CAI and SFB-L combination. Tumor growth was significantly suppressed in the combination group, and the efficacy of combination treatment was equivalent to that of the SFB-H monotherapy group. Furthermore, the combination group had reduced side effects compared with the SFB-H group, as indicated by weight preservation in mice. Our study illustrates that CAI enhances the antitumor activity of sorafenib in NSCLC and provides a novel strategy for NSCLC treatment., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Carboxyamidotrizole (CAI) has been reported to suppress the production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β and be effective in rats with adjuvant arthritis. The aim of this study was to investigate the role of CAI in inflammatory bowel disease (IBD). We assessed the effect of CAI in dextran sodium sulfate-induced colitis. Inflammation was scored histologically, and potential mediators of IBD were assessed by immunohistochemical and molecular biochemical approaches. CAI-treated colitis animals revealed much fewer signs of colitis with significantly decreased macroscopic and microscopic scores than vehicle-treated animals. CAI inhibited the production of TNF-α, IL-1β, and IL-6 in serum, supernatant of peritoneal macrophages, and lamina propria. CAI also decreased the expression of intercellular adhesion molecule-1 in colonic tissues. Furthermore, CAI prevented nuclear factor-κB (NF-κB) activation and inhibitor of nuclear factor-κBα phosphorylation and degradation. In addition, CAI showed a beneficial effect on colonic fibrosis, possibly by reducing the production of the fibrogenic cytokine transforming growth factor-β. The results support that CAI administration is effective in ameliorating experimental colitis and preventing colonic fibrosis. The inhibition of proinflammatory cytokines and adhesion molecules and suppression of NF-κB activation seem to contribute to this effect.

Carboxyamidotriazole (CAI) is a calcium influx inhibitor that is undergoing clinical trials for the treatment of various human cancers following the identification of its antiproliferative and antimetastatic activities. The exact mechanism of its action is not clearly understood, and whether it has other functions besides the established antitumor activity has not been reported either. In the present study, we demonstrate for the first time that CAI possesses anti-inflammatory and analgesic activities using a variety of animal models, including croton oil-induced ear edema, cotton-induced granuloma, rat adjuvant-induced arthritis, acetic acid-induced writhing, and the formalin test. We also show that CAI significantly inhibits local vascular permeability stimulated by vascular endothelial growth factor or histamine and decreases tumor necrosis factor-alpha and interleukin-1beta levels at the site of inflammation and in serums, which may contribute to the anti-inflammatory effect. These data suggest that CAI is a promising anti-inflammatory and analgesic agent, and they provide new insight into the biological activity of the drug.