Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies.

Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin's anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment.

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer.

BACKGROUND: Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. METHODS: We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. We tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. RESULTS: In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (i.e., BDNF, TNFα, FGF-2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1 in mammary adipose, and reduced phosphorylated FGFR indicating reduced FGF signaling in tumors. CONCLUSIONS: Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multi-factorial, and that weight maintenance during the peri-/postmenopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

Ghrelin and Cancer: Examining the Roles of the Ghrelin Axis in Tumor Growth and Progression.

Ghrelin, a hormone produced and secreted from the stomach, is prim arily known as an appetite stimulant. Recently, it has emerged as a potential regulator/biomarker of cancer progression. Inconsistent results on this subject make this body of literature difficult to interpret. Here, we attempt to identify commonalities in the relationships between ghrelin and various cancers, and summarize important considerations for future research. The main players in the ghrelin family axis are unacylated ghrelin (UAG), acylated ghrelin (AG), the enzyme ghrelin O-acyltransferase (GOAT), and the growth hormone secretagogue receptor (GHSR). GOAT is responsible for the acylation of ghrelin, after which ghrelin can bind to the functional ghrelin receptor GHSR-1a to initiate the activation cascade. Splice variants of ghrelin also exist, with the most prominent being In1-ghrelin. In this review, we focus primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts. Further understanding of the role of the ghrelin axis in tumor cell proliferation could lead to the development of novel therapeutic approaches for various cancers.

A sensitive HPLC-FLD method combined with multivariate analysis for the determination of amino acids in l-citrulline rich vegetables.

The proposed analytical method reports the separation and quantification of 21 amino acids including l-citrulline from fresh vegetables and commercial juices using a C8 column. Optimal separation conditions for amino acids analysis were obtained with 20 mM sodium acetate (solvent A) and water with organic modifier acetonitrile and methanol (solvent B; 18/50/32 V/V). The ideal pH and column temperature were found to be 5.40 and 35 °C, respectively. The LOD and LOQ values were obtained in the range of 0.02-0.19 ng/mL and 0.04-0.39 ng/mL for all amino acids respectively. Relative standard deviations (RSD) of intraday and interday analysis were found to be <2.7% and 7.9%, respectively. The recovery of amino acids were found be satisfactory for all the tested crops. The developed method was successfully used for the quantification of amino acids in six fresh vegetable juices including watermelon, cucumber, celery, calabaza squash, zucchini squash, yellow squash and commercial juices. Multivariate analysis was used to determine the significant differences in the amino acids profiles. l-citrulline content was highest in fresh watermelon juice (716.57 ± 24.80 µg/mL) and commercial watermelon lime juice (826.48 ± 34.48 µg/mL). The optimized analytical method is rapid, sensitive, accurate and reproducible for analysis of free amino acids including l-citrulline from different vegetable juices and other food products. To the best of our knowledge, this is the first report to separate OPA derivatives of amino acids using C8 column from watermelon, cucumber, zucchini squash, yellow squash, calabaza squash, and celery in a HPLC-FLD system.

Storage Stability of Dietary Nitrate and Phenolic Compounds in Beetroot (Beta vulgaris) and Arugula (Eruca sativa) Juices.

Nitrate and polyphenols from the diet may enhance the production and bioavailability of nitric oxide, a radical signaling molecule critical for cardiovascular health. Understanding the stability of these bioactives in beetroot and arugula juices is important for their functions. In this study, the stability of nitrate and phenolics in beetroot and arugula juices was measured for 32 days at different temperatures (25, 4, -20, and -80 °C). The levels of nitrate were measured by reversed-phase HPLC and initial levels were found to be 4965.34 ± 72.69 µg/mL for beetroot and 6310.20 ± 24.79 µg/mL for arugula. Interestingly, nitrate degradation started within 24 hr at 25 °C and after 4 days at 4 °C. At -20 °C and -80 °C, nitrate levels remained stable for one month. Total phenolics and free radical scavenging activity varied significantly during storage conditions. Beetroot juice at 25 °C, significant decrease in total phenolics and antioxidant activity was observed, whereas at 4, -20 and -80 °C, the levels remained relatively stable. By contrast, arugula juice at 25 and 4 °C, an increase in total phenolics and antioxidant activity were observed after one month. Furthermore, UPLC-HR-QTOF-MS analysis demonstrated that flavonoid glucosides were converted to their aglycones and lower phenolics, resulting in higher total phenolics and antioxidant activity during storage. In conclusion, beetroot and arugula juices required frozen conditions for long-term storage to prevent degradation of nitrate and to maintain their nutritional value. PRACTICAL APPLICATION: Beetroot and arugula juices have health-beneficial compounds such as nitrate and phenolics. Understanding the proper storage conditions can allow consumers to make informed choices that can help fresh juices to maintain their health promoting properties.