Apoptosis a major process of programmed cell death and in
Apoptosis, a major process of programmed cell death, and in response to many chemopreventive agents (Jeyamohan et al., 2016). In general, two major signaling pathways control apoptosis, namely, a pathway mediated by cell death receptor and a pathway mediated by mitochondrion, and possible drug targets that regulate cancer cell apoptosis have been widely studied (Fu et al., 2016). Therefor inducing cancer A-443654 apoptosis is an effective strategy for anti-cancer drugs (Xie et al., 2014). At present, many studies have focused on TCMs for their effects on cell apoptosis. Many studies showed that bioactive compounds from TCM can trigger the dysfunction of mitochondrial function in order to induce mitochondria-dependent apoptosis pathway (Liu et al., 2015). Among these process, Bcl-2 plays a central role of inducing the collapse of MMP, due to the Bcl-2 family proteins are involved in cell apoptosis through regulating mitochondrial membrane permeability (Wang et al., 2014). The Bcl-2 family mainly include anti-apoptotic protein whose member called Bcl-2 and pro-apoptotic protein whose member called Bax. Bcl-2 could bind to mitochondria and prevent the movement of cytochrome c from mitochondria into the cytoplasm (Prenek et al., 2017). On the other hand, pro-apoptotic member Bax could insert into the outer mitochondrial membrane and enlarge mitochondrial permeability, which promotes a decrease of ΔΨm and cytochrome c release (Kureel et al., 2016). In additional, it has been confirmed that the proportion of Bcl-2/Bax is an crucial determinant of susceptibility to apoptosis. Our data indicated that the Bcl-2/Bax proportion reduced in response to LA and increased the cytosolic cytochrome c level in a dose-dependent manner, suggesting that LA alters the ratio of anti-apoptotic and pro-apoptotic proteins of Bcl-2 family and mitochondrial membrane permeability to induce HepG2 apoptosis.
Caspases are activated and PARP is cleaved following the Bcl-2/Bax proportion decreases and cytochrome c is released into the cytoplasm (Yu et al., 2016). Caspase-9 is a trigger of the mitochondrial-mediated apoptosis pathway, which is activated by cytochrome c in the cytoplasm. It can subsequently activate Caspase-3 protein, which is the most important executioner protein in the mitochondrial-mediated apoptosis pathway, and eventually inactivation of PARP (Li et al., 2016). As a result, LA could increase the levels of cleaved caspases-9 and −3 as well as PARP, indicated that the mitochondrial-dependent apoptosis pathway is involved in LA-induced apoptosis in HepG2 cells.
Taken together, this study manifested that LA possessed cytotoxic activity by inducing apoptosis in HepG2 cells in vitro, which is consistent with our prior study (Ma et al., 2016). A proteomic analysis of the differentially expressed protein profiles and Western blotting analysis indicated that mitochondrial-related apoptosis proteins were associated with LA-induced apoptosis. The molecular mechanisms of LA on HCC can be summarized as shown in Fig. 9. Our results demonstrated that LA could induce HepG2 cells apoptosis via the activation of the mitochondrial-mediated apoptosis pathway. These findings would contribute to understand the molecular toxicity of LA, and provide valuable data for reasonable use of this drug.
Acknowledgments This work was financially supported by the National Natural Science Foundation of China: 81000878 and 81360270; Fundamental Research Funds for the Central Universities: lzujbky-2017-126; Talent innovation and entrepreneurship science and technology projects of Lanzhou city: 2014-RC-68; Chengguan District Science and Technology Project of Lanzhou city: 2016-7-6 and 2016-7-8.
Introduction Carboxylic polyether ionophores are extensively used as feed additives to control coccidiosis in the poultry industry and to promote the growth of various animals (Novilla, 1992; Dorne et al., 2013). Maduramicin, a monoglycoside polyether antibiotic, is one of the most extensively used anticoccidial drug that has been reported to be effective when mixed with poultry feed in a concentration of 5 ppm to prevent Eimeria spp. infections (Folz et al., 1988; Logan et al., 1993). In general, the marketed carboxylic ionophore products are effective and safe in target animal species when applied within the approved dosage ranges (Novilla, 2007). However, overdosage, misuse, and drug interactions have resulted in toxicity-related damage in target/non-target animals (i.e., broiler chickens, pigs, rabbits, cattle, sheep, horses, dogs, cats, and turkeys), as well as in humans who consume contaminated animal products or foods (Novilla, 1992; Oehme and Pickrell, 1999; Sharma et al., 2005; Shimshoni et al., 2014).