Natural Product Quercetin-3-methyl ether Promotes Colorectal Cancer Cell Apoptosis by Downregulating Intracellular Polyamine Signaling.

Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer. Increased polyamine metabolism is a common metabolic change in tumors. Thus, targeting polyamine metabolism for anticancer therapy, particularly polyamine blockade therapy, has gradually become a hot topic. Quercetin-3-methyl ether is a natural compound existed in various plants with diverse biological activities like antioxidant and antiaging. Here, we reported that Quercetin-3-methyl ether inhibits colorectal cancer cell viability, and promotes apoptosis in a dose-dependent and time-dependent manner. Intriguingly, the polyamine levels, including spermidine and spermine, in colorectal cancer cells were reduced upon treatment of Quercetin-3-methyl ether. This is likely resulted from the downregulation of SMOX, a key enzyme in polyamine metabolism that catalyzes the oxidation of spermine to spermidine. These findings suggest Quercetin-3-methyl ether decreases cellular polyamine level by suppressing SMOX expression, thereby inducing colorectal cancer cell apoptosis. Our results also reveal a correlation between the anti-tumor activity of Quercetin-3-methyl ether and the polyamine metabolism modulation, which may provide new insights into a better understanding of the pharmacological activity of Quercetin-3-methyl ether and how it reprograms cellular polyamine metabolism.

Quercetin-3-methyl ether inhibits esophageal carcinogenesis by targeting the AKT/mTOR/p70S6K and MAPK pathways.

Esophageal squamous cell carcinoma (ESCC) is highly prevalent in Asia, especially in China. Research findings indicate that nitrosamines, malnutrition, unhealthy living habits, and genetics contribute to esophageal carcinogenesis. Currently, the 5-year survival rate for ESCC patients remains low, owing in part to a lack of a clear understanding of mechanisms involved. Chemoprevention using natural or synthesized compounds might be a promising strategy to reduce esophageal cancer incidence. The epidermal growth factor receptor (EGFR) can activate downstream pathways including the phosphatidylinositol 3-kinase (PI3K) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathways. Among the important players, AKT and ERKs have an important relationship with cancer initiation and progression. Here, we found that phosphorylated (p)-AKT and p-ERKs were highly expressed in esophageal cancer cell lines and in esophageal cancer patients. Human phospho-kinase array and pull-down assay results showed that quercetin-3-methyl ether (Q3ME) is a natural flavonoid compound that interacted with AKT and ERKs and inhibited their kinase activities. At the cellular level, Q3ME attenuated esophageal cancer cell proliferation and anchorage-independent growth. Western blot analysis showed that this compound suppressed the activation of AKT and ERKs downstream signaling pathways, subsequently inhibiting activating protein-1 (AP-1) activity. Importantly, Q3ME inhibited the formation of esophageal preneoplastic lesions induced by N-nitrosomethylbenzylamine (NMBA). The inhibition by Q3ME was associated with decreased inflammation and esophageal cancer cell proliferation in vivo. Collectively, our data suggest that Q3ME is a promising chemopreventive agent against esophageal carcinogenesis by targeting AKT and ERKs.

Polyphenol-Rich Fraction from Larrea divaricata and its Main Flavonoid Quercetin-3-Methyl Ether Induce Apoptosis in Lymphoma Cells Through Nitrosative Stress.

Larrea divaricata is a plant with antiproliferative principles. We have previously identified the flavonoid quercetin-3-methyl ether (Q-3-ME) in an ethyl acetate fraction (EA). Both the extract and Q-3-ME were found to be effective against the EL-4 T lymphoma cell line. However, the mechanism underlying the inhibition of tumor cell proliferation remains to be elucidated. In this work, we analyzed the role of nitric oxide (NO) in the induction of apoptosis mediated by Q-3-ME and EA. Both treatments were able to induce apoptosis in a concentration-dependent and time-dependent manner. The western blot analysis revealed a sequential activation of caspases-9 and 3, followed by poly-(ADP-ribose)-polymerase cleavage. EA and Q-3-ME lowered the mitochondrial membrane potential, showing the activation of the intrinsic pathway of apoptosis. Q-3-ME and EA increased NO production and inducible NO synthase expression in tumor cells. The involvement of NO in cell death was confirmed by the nitric oxide synthases inhibitor L-NAME. In addition, EA and Q-3-ME induced a cell cycle arrest in G0/G1 phase. These drugs did not affect normal cell viability. This data suggested that EA and Q-3-ME induce an increase in NO production that would lead to the cell cycle arrest and the activation of the intrinsic pathway of apoptosis. Copyright © 2016 John Wiley & Sons, Ltd.

A fraction rich in phenyl propanoids from L. divaricata aqueous extract is capable of inducing apoptosis, in relation to H2O2 modulation, on a murine lymphoma cell line.

Leukemia and lymphoma are a group of heterogeneous neoplastic disorder of white blood cells characterized by the uncontrolled proliferation and block in differentiation of hematopoietic cells. Nowadays, there is an interest in therapy with drugs of plant origin because conventional medicine can be inefficient or also results in side effects. Larrea divaricata Cav., is a plant widely distributed in Argentina that possess antiproliferative and antioxidant activities reported. Nordihydroguaiaretic acid (NDGA) was previously found in the plant and related to both antiproliferative and pro-proliferative actions on a lymphoma cell line. In order to demonstrate whether the presence of NDGA may be beneficial or not in the antiproliferative action of the aqueous extract, the extract of L. divaricata was submitted to a fractionation and fractions with and without NDGA were studied in a murine lymphocitic leukemia cell line (EL-4) proliferation. The effect of the most active fraction was studied in relation to H2O2 modulation and the synergistic action between compounds, found in fractions, was analyzed. The presence of NDGA was not a detonator for pro-proliferative action and its presence could be beneficial in low concentrations allowing a synergist antiproliferative action with other compounds.

Chemical constituents of Nelumbinis Plumula / 中草药

Objective: To investigate the chemical constituents from the Seeds of Nelumbo nucifera. Methods: The chemical constituents were isolated by repeated silica gel chromatography, Sephadex LH-20 gel columns chromatography, medium pressure column chromatography, and semi-preparative liquid chromatography, and their structures were elucidated by chemical properties and spectroscopic analyses. Results: Thirteen compounds were identified to be p-methoxyphenylacetic acid (1), quercetin-3-O-α-L- arabinoside (2), apigenin-6-C-arabinoside-8-C-glucoside (3), naringenin (4), stigmast-4-en-3-one (5), quercetin-3-methyl ether (6), vitexin (7), cosmoslin (8), quercetin (9), apigennin (10), luteolin (11), kaempferol (12), and astragalin (13). Conclusion: Compounds 1-3, 5 and 6 are obtained from the plants of Nelumbo Adans for the first time, and compound 8 is obtained from Nelumbo plumula for the first time.

Chemical constituents of Opuntia milpa (I) / 中草药

Objective: To investigate the chemical constituents of Opuntia milpa. Methods: The compounds were isolated by repeated silica gel chromatography and were elucidated by chemical and spectral analyses. Results: Ten compounds were isolated from the ethyl acelate extraction of O. milpa and identified as β-sitosterol (1), 1-heptadecanol (2), 5-hyadroxymemyl-2-furancarboxaldehyde (3), syringaldehyde (4), vanillin (5), p-hydroxybenzaldehyde (6), coniferyl aldehyde (7), p-hydroxyl-cinnamaldehyde (8), quercetin-3-methyl ether (9), and 2,6-dimethoxyphenol (10). Conclusion Compounds 3-10 are isolated from O. milpa for the first time.