Induction of CYP1A1 only inside the colon of rats incubated with Uro-A and Uro-B dissolved in PBS and not in sunflower oil (49). The in situ benefits points to a vital effect from the dissolving media within the activities of the urolithins. An additional study also confirmed the possible inhibitory effects of various urolithins metabolites on CYP1. According to Kasimsetty et al. (70). Uro-A (IC50 , 56.7 2.6 ), Uro-B (IC50 , 58.six 4.two ), and Uro-C (IC50 , 74.eight 2.29 ) exerted dosedependent inhibition of TCDD-induced CYP1 enzymes on HT29 cells. These metabolites, like Uro-D, induced a dose and time-dependent antiproliferative action on HT-29 cells with IC50 values in the range of 31678 . These weak albeit antiproliferative potentials are specific to cancer cells only and are connected with apoptosis induction (70). MMP-1 site urolithin A has been showed to exert a synergistic action with oxaliplatin on colon cancer cells. Oxaliplatin is a regular chemotherapeutic drug utilized for therapy against colon cancer. Urolithin A inside a time and dose-dependent manner (39.2 , 48 h, and 19.six , 72 h) inhibited the growth of HCT116 cells and halted cell cycle progression in the G2 /M phase. The UroA development inhibitory impact on HCT 116 cells is p53-dependent at a low dose and p53 independent at a higher dose. Uro- A also showed p53-dependent synergistic action with oxaliplatin as evidenced from the reported combinatorial indices (CI) of 1 (58). A CI value 1 denotes synergism, values 1 indicates antagonism and values = 1 denotes an addictive impact (117). These study information imply that urolithin could help oxaliplatin chemotherapy against colon cancer. Furthermore, cancer cellsFrontiers in Nutrition | www.frontiersin.orgJune 2021 | Volume 8 | ArticleAl-Harbi et al.Urolithins in Cancer Preventionrely on aerobic glycolysis for glucose metabolism. This metabolic reprogramming from oxidative phosphorylation to glycolysis has been recommended to market tumor cell growth and malignancy (118) and recognized as an emerging hallmark of cancer (104). An enhanced aerobic lactic acid production by means of glycolysis is associated with drug resistance in LoVo colon carcinoma cells (119). As a result, an interruption of cellular bioenergetics in tumor cells can ALK4 Molecular Weight sensitize the cell to chemotherapy and inhibit tumor growth by means of power depletion. Employing extracellular flux evaluation, Norden and Heiss (58), showed that Uro- A influenced cellular bioenergetics in HCT 116 cells in a p53dependent manner through a reduction in glycolytic possible. This lowered glycolytic potential is associated with all the induction of TP53-induced glycolytic regulatory phosphatase (TIGAR) in WT HCT116 cells. TIGAR can be a damaging regulator of glycolysis. Its overexpression leads to a lower in cellular fructose-2,6bisphosphate levels, resulting in the inhibition of glycolysis (120). Thus, this study points to a different Uro-A antiploriferative potentials against cancer cells. Uro-A’s combinational therapy with 5-Fluorouracil (5-FU) and 5-deoxy-5-fluorouridine (5 DFUR) has been examined on colon cancer cell lines. The 5 DFUR is usually a pro-drug and also an intermediate of 5-FU. The co-treatment of 5-FU with Uro-A improved the sensitivity of 5-FU in Caco-2 (1.two and two.4-fold), SW480 (1.6 and two.4-fold), and in HT-29 cells (1.3 and 1.7-fold) in the presence of ten and 20 , 72 h of Uro-A, respectively. The exact same increased sensitivity was observed when Uro-A at a nontoxic concentration of ten or 20 was cotreated with five DFUR in Caco-2 (1.three and.
