Abstract. Two enzymes in human plasma capable of hydrolysing aspirin (‘aspirin esterases’) were isolated (by ion exchange and gel chromatography) and characterized, since their activity has been reported to be important in certain disease/therapeutic situations. The optimum pH and calcium concentration for plasma aspirin esterases were 80 and 5 mmol/1 respectively. The main enzymic activity (enzyme ‘C’) was associated with plasma cholinesterases. This component had a Km of 6‐5 mmol/1 for aspirin and a Kmax of 0–27 /imol salicylate/mg protein/min at pH 80 (Ca2+ present). It was not acetylated by aspirin but was inhibited by anti‐cholinesterase agents (eserine, echothiophate) and the neuromuscular blocking agent, decameth‐onium. The other enzymic component in plasma was albumin esterase. The sex difference in aspirin esterase activity in normal individuals previously reported by Menguy and co‐workers [1] was re‐investigated since it appeared that they had employed non‐optimal assay conditions. No significant differences were observed between the sexes in either normal individuals or patients with rheumatoid arthritis when the enzyme was assayed at either pH 7‐4 or the optimal pH of 80 (with Ca2+ added). The plasma albumin esterase activity was, however, markedly depressed in patients with alcoholic liver cirrhosis when assayed at pH 7‐4 and 80. Plasma aspirin esterases were elevated in nine rheumatoid arthritic patients receiving gold salt or D(‐)penicil‐lamine. Aspirin esterase 'C activity was negatively correlated with pain score in the plasma of female but not male rheumatoid arthritics. Also the percentage activation by calcium of aspirin esterase was correlated with the concentration of plasma calcium indicating that small changes in plasma calcium concentration may markedly affect enzymic activity. These results suggest that certain drugs (anti‐cholinesterase agents), disease states (e.g. alcoholic liver cirrhosis) or genetic deficiences (e.g. inactive pseudo‐cholinesterase) may be potentially important in the pharmacological and iatrogenic activities of aspirin.
Background: Several preclinical studies indicate that secoisolariciresinol diglycoside (SDG), a polyphenolic plant lignin found most abundantly in flaxseeds, inhibits the progression of both estrogen receptor (ER) positive and negative mammary tumors. SDG is metabolized by gut bacteria into the biologically active metabolites enterolactone (ENL) and enterodiol (END), which are known to have anti-estrogenic activity. However, the mechanisms mediating SDG's anti-tumor effects remain poorly understood. Methods: In a dose-determination pilot study linked to an ongoing clinical trial of SDG in women at high risk for breast cancer, 18 week old C57BL/6 mice were randomized to a control diet or SDG-supplemented diets (25 or 74 mg/kg of food) for 8 weeks prior to euthanization, and the levels of serum and tissue SDG metabolites (particularly ENL and END), metabolic hormones and inflammatory markers were measured. In an ongoing tumor study, 12-week old C57BL/6 and foxn1 nu/nu mice were randomized to the control or control plus SDG (100 mg/kg of food, a dose projected to match ENL and END metabolite levels achieved in the clinical trial) diet regimen. After 8 weeks on diet, they will receive orthotopic injections of E0771 mouse mammary tumor cells or BT-483 human breast cancer cells (both ER positive), continuing on the same diets until euthanization. Cell culture studies examining the impact of biologically relevant concentrations of ENL and END on E0771 and BT-483 cells are also in progress. Results: In comparison to those maintained on the control diet, the higher dose SDG diet reduced estrogen and pro-inflammatory signaling in the pilot study mice, as evidenced by higher interleukin 10 and lower C-reactive protein mammary fat pad expression as well as lower circulating levels of the adipokines leptin and resistin, which have been linked to chronic inflammation. High dose SDG also decreased serum insulin and glucose levels, indicating improved metabolic function. Because serum ENL and END levels in the pilot study did not reach those achieved in the SDG clinical trial, a 100 mg/kg SDG dose was chosen for the tumor study. Cell culture studies indicate that ENL (150 nM) inhibits E0771 and BT-483 cell proliferation and ER alpha:beta expression ratio. Conclusions: Preliminary data suggests that the anti-tumor effects of SDG's metabolites may be mediated through multiple mechanisms, including improvements in metabolic function and inflammatory signaling as well as modulation of breast cancer cell gene expression. The results of the ongoing tumor study will inform the design of additional cell culture studies aimed at further defining these mechanisms. Citation Format: Bowers LW, Ford NA, Rossi EL, Shamsunder MG, Kimler BF, Fabian CJ, Hursting SD. The impact of the plant lignin secoisolariciresinol diglycoside on preclinical models of estrogen receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-28.
Background: In the U.S., the prevalence of obesity has reached epidemic proportions, with over two-thirds of the population being overweight and one-third being obese. Epidemiological data suggests that women who maintain a healthy weight have a lower risk of developing breast cancer and a better prognosis if diagnosed than those that are obese. Of the various breast cancer subtypes, claudin-low is associated with poor prognosis and resistance to standard chemotherapeutic regimens, Our lab has previously shown that a diet-induced obesity (DIO) regimen enhanced tumor progression and promoted the epithelial to mesenchymal transition (EMT)- and tumor–initiating cell (TIC)-associated markers in a murine claudin-low tumor model. Resveratrol is an antiinflammatory natural polyphenol that can decrease expression of markers indicative of stem cells and prevent EMT. Therefore, we hypothesized that resveratrol would impede the protumorigenic nature of obesity through its effects on EMT in a stem cell-enriched tumor model. The present study evaluated the effect of resveratrol supplementation on tumor growth in a DIO regimen in the murine M-Wnt breast cancer model. Methods: Eight-week-old ovariectomized female C57BL/6 mice were randomized (n = 15 per group) to receive one of the following three dietary regimens: control diet (10%kcal from fat), DIO regimen (60% kcal from fat), or DIO regimen supplemented with resveratrol (0.5% wt/wt). Mice consumed the experimental diets ad libitum for 6 weeks prior to orthotopic injection of 2.5×105 GFP-luciferase labeled M-Wnt murine mammary tumor cells (derived from MMTV-Wnt-1 tumor). Transplanted tumors grew for five additional weeks while diets were continued. Tumors were measured weekly with calipers and in vivo growth was monitored by the In Vivo Imaging System (IVIS). Mice were killed, serum was collected and stored at -80C and tissues were either fixed in 10% neutral-buffered saline or or flash-frozen. Results: Using the M-Wnt model of claudin-low breast cancer, we found that resveratrol supplementation significantly reduced body weight (p<0.0001), caloric intake (p<0.05) and tumor burden (weight and volume)(p = 0.021 and p = 0.007, respectively) within the DIO regimen although it had no effect on fasting glucose. Control maintained a significantly lower body fat percentage (p<0.001) than DIO regardless of resveratrol supplementation. Despite weighing significantly more (p<0.0001), mice that consumed the resveratrol-supplemented diet had comparable tumor burden to the lower calorie, control diet. Discussion: We conclude that resveratrol supplementation circumvented the protumorigenic nature of the DIO regimen equivalent to the lower calorie, lower fat control diet. Thus, dietary supplementation with resveratrol in the high-risk, obese population could break the obesity-cancer link. Keywords: epithelial to mesenchymal transition, resveratrol, mammary tumor, diet-induced obesity, stem cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-07.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.