Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-κB and activating SIRT1

Abstract

Cancer cachexia is a complex disorder characterized by inflammatory responses, and it is associated with poor performance status and high mortality rate of cancer patients. Carboxyamidotriazole (CAI), a noncytotoxic chemotherapy agent, shows anti-inflammatory features in the treatment of many diseases. Here, we investigated the preventive and therapeutic effects of CAI on muscle loss that occurred in mice with advanced Lewis lung carcinoma (LLC). The carcass weights of CAI-treated mice were significantly higher than that of mice in the vehicle group from Day 19 to the end of the study. The gastrocnemius and epididymal adipose tissue weights were also increased by CAI treatment. The protective mechanisms might be attributed to the following points: CAI treatment inhibited the proteolysis in muscles by decreasing expressions of muscle-specific FoxO3 transcription factor and ubiquitin E3 ligases (MuRF1 and atrogin1). Moreover, CAI restricted the NF-κB signaling, downregulated the level of TNF-α in muscle and both TNF-α and IL-6 levels in serum, directly stimulated SIRT1 activity in vitro, and increased SIRT1 content in muscle. These results indicate that CAI can alleviate muscle wasting and is a promising drug against lung cancer cachexia.

Carboxyamidotriazole Synergizes with Sorafenib to Combat Non–Small Cell Lung Cancer through Inhibition of NANOG and Aggravation of Apoptosis

“…6E, the carcass weight exhibited a slightly different tendency: 26.59 g (CAI), 26.05 g (combination), 25.04 g (SFB-L), 24.82 g (PEG400), and 24.80 g (SFB-H). Consistent with our previous observation that CAI could ameliorate cancer-associated cachexia (Chen et al, 2017), the CAI and combination treatment groups showed potential to maintain the body weight of tumor-bearing mice compared with the PEG400 group. It is noteworthy that the average carcass weight in the combination group was significantly heavier than that in the SFB-H group (Fig.…”

“…Although CAI exhibited mild anticancer properties in some clinical trials, the majority of toxicities noted were grade I, which means CAI was generally well tolerated (Hussain et al, 2003;Desai et al, 2004;Dutcher et al, 2005;Mikkelsen et al, 2007). In addition, CAI exhibited a protective role in treating cancer-associated cachexia by inhibiting muscle proteolysis and restraining inflammatory responses (Chen et al, 2017), which implies that CAI may synergize with other anticancer drugs through limiting chemotherapy-induced weight loss. In chronic myeloid leukemia cells, CAI was shown to reduce cell viability and induce apoptosis in a redox-mediated way (Alessandro et al, 2008;Corrado et al, 2011).…”

Molecular Basis for the Therapeutic Effects of Exercise on Mitochondrial Defects

“…Most studies indicate that PGC-1α protein is significantly reduced with cancer cachexia, while genome-wide transcriptome datasets show that PGC-1β gene expression is similarly diminished (Fontes- Puppa et al, 2014;Sheng et al, 2017;Van Der Ende et al, 2018). Activators of PGC-1α SirT1 and MEF2C, are also found to decrease in cachectic muscle, as well as downstream targets, ERRα and Tfam, altogether indicating impaired drive for organelle synthesis (White et al, 2011;Shum et al, 2012;Zhuang et al, 2016;Chen et al, 2017;Van Der Ende et al, 2018). Indeed, it appears that the suppression of PGC-1α is a key event in the progression of cancer cachexia and is directly related to elevations in circulating IL-6 (Baltgalvis et al, 2008;White et al, 2012).…”

Blockade of IDO-kynurenine-AhR pathway promotes cell apoptosis in carboxyamidotriazole-induced tumor cell dormancy-apoptosis oscillation

“…Carboxyamidotriazole (CAI) is an inhibitor of calcium in ux and has shown antiangiogenic, antiproliferative, and antimetastatic properties in preclinical studies [14][15][16][17]. In addition, CAI exhibited a protective role in treating cancer-associated cachexia and had good synergistic effect with several rstline anti-cancer drugs [18,19]. In the early stage of tumorigenesis, CAI exerted a signi cant anti-cancer effect but in the stage of tumor relapse or progression, the role of CAI was relatively weakened, which can be observed in our animal experiments and previous clinical studies [20,21].…”