Chlorogenic acid an abundant polyphenol found in coffee

Chlorogenic WM-2474 receptor (7), an abundant polyphenol found in coffee and the human diet, has various biological activities including antioxidant and anticancer effects [54]. Jiang et al. reported that compound 7 had a selective cytotoxic activity on human oral tumor cells (HSG, HSC-2) as compared with normal cells (HGF) [55]. This compound induced apoptosis of oral tumor cells characterized by DNA fragmentation and activation of caspase activity. The authors suggested that the proapoptotic effect of 7 is probably caused by a H2O2-mediated oxidation reaction [55]. In another study, chlorogenic acid inhibited the viability of human colon cancer (HCT116 and HT29) cells by inducing the intracellular ROS production, S-phase arrest and extracellular signal-related kinase (ERK) inactivation [56]. Recently, Yan et al. reported that chlorogenic acid inhibited the growth of hepatocellular carcinoma (HepG2) cells in vitro and the progression of HepG2 xenograft in vivo[57]. These effects were probably associated with the inactivation of ERK and the imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in HepG2 cells and in the extracellular matrix [57]. Piceatannol (8) was reported as having dual effects of chemoprevention and cancer inhibition [58]. Lee et al. showed that 8 at 10μM induced G1 phase arrest in androgen-insensitive DU145 prostate cancer cells via an inhibition of cyclin-dependent kinase (CDK) activity [59]. The effective concentration of 8 in this study was significantly lower than that previously reported by Wolter et al.[60] [S phase accumulation in Caco-2 colon cancer cells treated with (8) at 100μM]. In breast cancer cells, 8 had no effect on cell viability up to 10μM, but it efficiently reduced serum-induced cell invasion in a concentration-dependent manner (2, 5, 10μM) [61]. Recently, Zhang et al. showed that 8 inhibited HCT116 and HT29 colorectal cancer cell proliferation in a concentration- and time-dependent manner [62], through increased apoptosis secondary to increased miR-129 expression and decreased Bcl-2 expression, a target of miR-129 [62]. Regarding natural compounds, they have pleiotropic effects beyond arginase inhibition which could also be involved in their anticancer activities. As presented above (Fig. 1), the high level of ROS damages macromolecules, cells and tissues, and this is an initial event for carcinogenesis promotion. ROS could be formed by uncoupled NOS secondary to increased arginase activity. Natural polyphenols are well-known for their proper antioxidant property [63], which could reduce oxidative stress and participate in cancer prevention. Although many studies have demonstrated the cytotoxic effect of these compounds against various types of cancer, it is striking that their anticancer effect has never been systematically related to their inhibitory activity on arginase so far. Therefore, it would be interesting in future studies to determine whether their anticancer effect might be related to their arginase inhibitory effect.
Concluding remarks and future perspectives Struggling against cancer and resistance of cancer means there is a need for new drugs that are more potent, tumor-specific and less toxic. Research over the past decades has unearthed arginase as a promising target for treatment of various cancers. Indeed, arginase regulates different biological pathways including polyamine synthesis, NO production and immune responses. With growing knowledge on structures and functions of arginase, the research of new arginase inhibitors has been accelerated. Among potent synthetic inhibitors, several candidates have been reported for their good anticancer effects, which were directly attributed to arginase inhibition. Besides, natural products with varied structures inhibited the activity of arginase, and some of them also showed their antitumor capacities but, unfortunately, the causal link between these two effects has never been studied. Until now, no arginase inhibitor has been approved as a drug for cancer treatment. However, one candidate [CB-1158 (10)] has gained approval for Phase I clinical trials in patients with solid tumors. Therefore, research of new potent arginase inhibitors is very hopeful for the development of novel anticancer agents, for which a rational strategy including in vitro, in silico and in vivo approaches should be used to effectively figure out a new lead compound.