Grape Polyphenols Inhibit Akt/Mammalian Target of Rapamycin Signaling and Potentiate the Effects of Gefitinib in Breast Cancer

a Department of Biochemistry, School of Medicine , University of Puerto Rico , Medical Sciences Campus , San Juan , Puerto Rico.
Nutrition and Cancer (Impact Factor: 2.32). 10/2012; 64(7):1058-69. DOI: 10.1080/01635581.2012.716898
Source: PubMed


We recently reported that a combination of dietary grape polyphenols resveratrol, quercetin, and catechin (RQC), at low concentrations, was effective at inhibiting metastatic cancer progression. Herein, we investigate the molecular mechanisms of RQC in breast cancer and explore the potential of RQC as a potentiation agent for the epidermal growth factor receptor (EGFR) therapeutic gefitinib. Our in vitro experiments showed RQC induced apoptosis in gefitinib-resistant breast cancer cells via regulation of a myriad of proapoptotic proteins. Because the Akt/mammalian target of rapamycin (mTOR) signaling pathway is often elevated during development of anti-EGFR therapy resistance, the effect of RQC on the mTOR upstream effector Akt and the negative regulator AMP kinase (AMPK) was investigated. RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells. Combined RQC and gefitinib decreased gefitinib resistant breast cancer cell viability to a greater extent than RQC or gefitinib alone. Moreover, RQC inhibited Akt and mTOR and activated AMPK even in the presence of gefitinib. Our in vivo experiments showed combined RQC and gefitinib was more effective than the individual treatments at inhibiting mammary tumor growth and metastasis in nude mice. Therefore, RQC treatment inhibits breast cancer progression and may potentiate anti-EGFR therapy by inhibition of Akt/mTOR signaling.

Download full-text


Available from: Suranganie Dharmawardhane, Oct 29, 2015
  • Source
    • "Moreover, polyphenols, as antioxidants, also induce apoptosis in neutrophils (19), and liver (20) and breast (21) cancer cells. In this regard, salidroside inhibits survival signals, such as the Akt phosphorylation and mammalian target of the rapamycin pathway, and destructs mitochondrial integrity (20,21). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is important in carcinogenesis and metastasis. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant properties. The aim of the present study was to investigate the roles of salidroside in cell proliferation, the cell cycle, apoptosis, invasion and epithelial‑mesenchymal transition (EMT) in A549 cells. The human alveolar adenocarcinoma cell line, A549, was incubated with various concentrations of salidroside (0, 1, 5, 10 and 20 µg/ml) and cell proliferation was detected by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay. Propidium iodide (PI) staining was used to determine the cell cycle by flow cytometry. Cell apoptosis was detected by Annexin V‑fluorescein isothiocyanate and PI double‑staining, and tumor invasion was detected by Boyden chamber invasion assay. Western blot analysis was performed to detect the expression of EMT markers, Snail and phospho‑p38. The results showed that salidroside significantly reduced the proliferation of A549 cells, inhibited cell cycle arrest in the G0/G1 phase and induced apoptosis. Salidroside inhibited transforming growth factor‑β‑induced tumor invasion and suppressed the protein expression of Snail. As an antioxidant, salidroside inhibited the intracellular reactive oxygen species (ROS) formation in a dose‑dependent manner in A549 cells, and depletion of intracellular ROS by vitamin C suppressed apoptosis by salidroside treatment. Salidroside was also found to inhibit the expression of phospho‑p38 in A549 cells. In conclusion, salidroside inhibits cell proliferation, the cell cycle and metastasis and induces apoptosis, which may be due to its interference in the intracellular ROS generation, thereby, downregulating the ROS‑phospho‑p38 signaling pathway.
    Oncology letters 04/2014; 7(4):1159-1164. DOI:10.3892/ol.2014.1863 · 1.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the advances in biomedical research and clinical applications, cancer remains a leading cause of death worldwide. Given the limitations of conventional chemotherapeutics, including serious toxicities and reduced quality of life for patients, the development of safe and efficacious alternatives with known mechanism of action is much needed. Prevention of cancer through dietary intervention may hold promise and has been investigated extensively in the recent years. AMP-activated protein kinase (AMPK) is an energy sensor that plays a key role in the regulation of protein and lipid metabolism in response to changes in fuel availability. When activated, AMPK promotes energy-producing catabolic pathways while inhibiting anabolic pathways, such as cell growth and proliferation - thereby antagonizing carcinogenesis. Other anti-cancer effects of AMPK may include promoting autophagy and DNA repair upon UVB damage. In the last decade, interest in AMPK has grown extensively as it emerged as an attractive target molecule for cancer prevention and treatment. Among the latest developments is the activation of AMPK by naturally occurring dietary constituents and plant products - termed phytochemicals. Owing to their efficacy and safety, phytochemicals are considered as an alternative to the conventional harmful chemotherapy. The rising popularity of using phytochemicals for cancer prevention and therapy is supported by a substantial progress in identifying the molecular pathways involved, including AMPK. In this article, we review the recent progress in this budding field that suggests AMPK as a new molecular target in the prevention and treatment of cancer by phytochemicals.
    Frontiers in Oncology 07/2013; 3:175. DOI:10.3389/fonc.2013.00175
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The cellular mechanisms and proximal targets responsible for resveratrol’s biological activity in mammalian cells are a subject of continued debate amongst the scientific community. One of the earliest activities attributed to resveratrol was that of an estrogen receptor agonist. In this chapter we highlight the striking parallels that exist between the effects elicited by resveratrol and its derivatives, and those associated with estrogen, under a variety of experimental conditions. We discuss other prevalent mechanisms that have been put forward to account for resveratrol’s cellular and systemic effects, including direct interactions with sirtuins, AMPK activation, and phosphodiesterase inhibition. In each instance we relate these mechanisms to estrogen signalling pathways, and build the argument that resveratrol’s properties as an estrogen receptor agonist are central to its biological activities.
    Bioactive Polyphenols from Wine Grapes, 01/2013: pages 27-52; , ISBN: 978-1-4614-6967-4
Show more