Study of quercetin and fisetin synergistic effect on breast cancer and potentially involved signaling pathways

Naturally-derived drugs have drawn much attention in recent decades. Efficiency, lower toxicity, and economic reasons are some of their advantages that justify this broad range of administration for different diseases, including cancer. If we can find a specific combination that boosts the effects of their single therapy, leading to synergism effect, increased efficiency, and decreased toxicity, they can act even better. Quercetin and fisetin, two well-known flavonoids, have been used to fight against various cancers. In this study, we investigated their possible synergism quercetin and fisetin on MCF7, MDA-MB-231, BT549, T47D, and 4T1 breast cancer cell lines. Then the optimum combined dose was used to study their impacts on wound healing abilities and clonogenic properties. The real-time qPCR was used to study the expression of their validated downstream effectors in predicted pathways. A significant synergism effect (p < .01, combination index: <1) was observed for all cell lines. Combination therapy was significantly more effective in colony formation (p < .0001) and wound healing assays (p < .001) compared to single therapies. The expression level of potential effectors was also showed a greater change. In vivo study confirmed the in vitro results and showed how significantly (p < .001) their synergism promotes their singular function in inhibiting cancer progression. The breast cancer mouse models receiving combined therapy lived longer with higher average body weight and smaller tumor sizes. These results exhibit that quercetin and fisetin inhibit cancer cell proliferation, migration and colony formation synergistically, and matrix metalloproteinase signaling and apoptotic pathways are relatively responsible for inhibitory activities.     

Isopongaglabol and 6-methoxyisopongaglabol,two new hydroxyfuranoflavones from Pongamia glabra

Isopongaglabol and 6-methoxyisopongaglabol, two new hydroxyfuranoflavones, together with two furanoflavones 5-methoxyfurano(8,7-4″,5″)flavone and 5-methoxy-3′,4′-methylenedioxyfurano(8,7-4″,5″)flavone, two simple flavones, desmethoxykanugin and fisetin tetramethyl ether, a chromenoflavanone, ovalichromene B, two triterpenes, cycloart-23-ene-3β,25-diol and friedelin, and β-sitosterol-β-d-glucoside were isolated from the petrol and CHCl₃ extracts of the flowers of Pongamia glabra. The structures of isopongaglabol and 6-methoxyisopongaglabol have been established as 4′-hydroxyfurano(8,7-4″,5″)flavone and 4′-hydroxy-6-methoxyfurano(8,7-4″,5″)flavone, respectively, on the basis of the spectral evidence and they have been confirmed by synthesis.     

Fisetin provides antidepressant effects by activating the tropomyosin receptor kinase B signal pathway in mice

Depression has been associated with a low‐grade chronic inflammatory state, suggesting a potential therapeutic role for anti‐inflammatory agents. Fisetin is a naturally occurring flavonoid in strawberries that has anti‐inflammatory activities, but whether fisetin has antidepressant effects is unknown. In this study, we exposed mice to spatial restraint for 2 weeks with or without treatment with fisetin. Immobility time in the forced swimming and tail suspension test after this restraint increased in the untreated group, but this increase did not occur in the fisetin group. We administered fisetin to Abelson helper integration site‐1 (Ahi1) knockout mice, which have depressive phenotypes. We found that fisetin attenuated the depressive phenotype of these Ahi1 knockout mice. We further investigated the potential mechanism of fisetin's antidepressant effects. Because TrkB is a critical signaling pathway in the mechanisms of depression, we examined whether phosphorylated TrkB was involved in the antidepressant effects of fisetin. We found that fisetin increased phosphorylated TrkB level without altering total TrkB; this increase was attenuated by K252a, a specific TrkB inhibitor. Taken together, our results demonstrated that fisetin may have therapeutic potential for treating depression and that this antidepressant effect may be mediated by the activation of the TrkB signaling pathway.

     

The actions of fisetin on glucose metabolism in the rat liver

Fisetin is a flavonoid dietary ingredient found in the smoke tree (Cotinus coggyria) and in several fruits and vegetables. The effects of fisetin on glucose metabolism in the isolated perfused rat liver and some glucose‐regulating enzymatic activities were investigated. Fisetin inhibited glucose, lactate, and pyruvate release from endogenous glycogen. Maximal inhibitions of glycogenolysis (49%) and glycolysis (59%) were obtained with the concentration of 200 µM. The glycogenolytic effects of glucagon and dinitrophenol were suppressed by fisetin 300 µM. No significant changes in the cellular contents of AMP, ADP, and ATP were found. Fisetin increased the cellular content of glucose 6‐phosphate and inhibited the glucose 6‐phosphatase activity. Gluconeogenesis from lactate and pyruvate or fructose was inhibited by fisetin 300 µM. Pyruvate carboxylation in isolated intact mitochondria was inhibited (IC₅₀ = 163.10 ± 12.28 µM); no such effect was observed in freeze‐thawing disrupted mitochondria. It was concluded that fisetin inhibits glucose release from the livers in both fed and fasted conditions. The inhibition of pyruvate transport into the mitochondria and the reduction of the cytosolic NADH‐NAD⁺ potential redox could be the causes of the gluconeogenesis inhibition. Fisetin could also prevent hyperglycemia by decreasing glycogen breakdown or blocking the glycogenolytic action of hormones. Copyright © 2010 John Wiley & Sons, Ltd.     

Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation

Many of the physiological benefits attributed to flavonoids are thought to stem from their potent antioxidant and free radical scavenging properties. Recently, it was shown that flavonoids protect nerve cells from oxidative stress by multiple mechanisms, only one of which is directly related to their antioxidant activity, suggesting that specific flavonoids may have other properties that could make them useful in the treatment of conditions that lead to nerve cell death. In particular, it was asked if any flavonoid could mimic neurotrophic proteins. To examine this possibility, we looked at the ability of flavonoids to induce nerve cell differentiation using PC12 cells. PC12 cells were treated with a variety of flavonoids to determine if there was a correlation between their neuroprotective activity and their neurite outgrowth-promoting activity. In addition, the signaling pathways required for flavonoid-induced differentiation were examined. We found that only a small subset of the flavonoids that were neuroprotective could induce neurite outgrowth by an extracellular signal-regulated kinase-dependent process. There was a strong correlation between the concentrations of the flavonoids that were neuroprotective and the concentrations that induced differentiation. These results suggest that the consumption of specific flavonoids could have further beneficial effects on nerve cells following injury, in pathological conditions or in normal aging.     

Fisetin induces apoptosis in breast cancer MDA‐MB‐453 cells through degradation of HER2/neu and via the PI3K/Akt pathway

Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in breast cancer. The major snag faced by the human population is the development of chemoresistance to HER2 inhibitors by advanced stage breast cancer cells. Moreover, recent researchers focussed on fisetin as an antiproliferative and chemotherapeutic agent. Therefore, this study was intended to analyze the effects of fisetin on HER2/neu‐overexpressing breast cancer cell lines. Our results depicted that fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half‐life, decreasing enolase phosphorylation, and alteration of phosphatidylinositol 3‐kinase/Akt signaling.