ABSTRACT
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.
Subject(s)
Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Nanog Homeobox Protein/antagonists & inhibitors , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Triazoles/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/physiology , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , Drug Synergism , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Nanog Homeobox Protein/metabolism , Niacinamide/administration & dosage , Sorafenib , Xenograft Model Antitumor Assays/methodsABSTRACT
OBJECTIVE: To explore the potential anti-inflammatory and analgesic activities of carboxyamidotriazole (CAI). METHODS: A variety of animal models, including the croton oil-induced ear edema, the cotton-induced granuloma, the rat adjuvant-induced arthritis, were used to evaluate anti-inflammatory effect of CAI. Vascular endothelial growth factor (VEGF)--or histamine-stimulated local vascular permeability in mouse modulated by CAI was also determined. In addition, we assessed the effect of CAI on the levels of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-beta) at the site of inflammation and in sera. Moreover, antinociceptive effect of CAI on inflammatory pain was assessed using acetic acid-induced writhing model and the formalin test. RESULTS: CAI significantly inhibited acute and chronic phases of inflammation, reduced VEGF or histamine-induced vascular permeability, and showed marked inhibition of proinflammatory cytokines such as TNF-alpha and IL-1 beta. CAI also showed potential therapeutic effect on peripheral inflammatory pain. CONCLUSION: CAI is a promising anti-inflammatory and analgesic agent.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Triazoles/pharmacology , Animals , Drug Evaluation, Preclinical , Female , Male , Mice , Mice, Inbred ICR , Rats , Rats, WistarABSTRACT
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.