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      Focus on Formononetin: Anticancer Potential and Molecular Targets

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          Abstract

          Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover ( Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for the past decade as strong evidence on promoting apoptosis and against proliferation suggests for its use as an anticancer agent against diverse cancers. These anticancer properties are observed in multiple cancer cell models, including breast, colorectal, and prostate cancer. Formononetin also attenuates metastasis and tumor growth in various in vivo studies. The beneficial effects exuded by formononetin can be attributed to its antiproliferative and cell cycle arrest inducing properties. Formononetin regulates various transcription factors and growth-factor-mediated oncogenic pathways, consequently alleviating the possible causes of chronic inflammation that are linked to cancer survival of neoplastic cells and their resistance against chemotherapy. As such, this review summarizes and critically analyzes current evidence on the potential of formononetin for therapy of various malignancies with special emphasis on molecular targets.

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          Most cited references137

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          20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.

          The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment.
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            Revisiting the hallmarks of cancer.

            The hallmarks of cancer described by Hanahan and Weinberg have proved seminal in our understanding of cancer's common traits and in rational drug design. Not free of critique and with understanding of different aspects of tumorigenesis coming into clearer focus in the recent years, we attempt to draw a more organized and updated picture of the cancer hallmarks. We define seven hallmarks of cancer: selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation, while highlighting some considerations for the future of the field.
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              Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors.

              Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade. Copyright © 2013 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                01 May 2019
                May 2019
                : 11
                : 5
                : 611
                Affiliations
                [1 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; samantha.ong@ 123456u.nus.edu (S.K.L.O.); phcsmk@ 123456nus.edu.sg (M.K.S.); phcfanl@ 123456nus.edu.sg (L.F.)
                [2 ]Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA; SFraser78637@ 123456med.lecom.edu
                [3 ]Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia; frank.arfuso@ 123456curtin.edu.au
                [4 ]Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
                Author notes
                [* ]Correspondence: ksahn@ 123456khu.ac.kr (K.S.A.); phcgs@ 123456nus.edu.sg (G.S.); abishayee@ 123456lecom.edu or abishayee@ 123456gmail.com (A.B.); Tel.: +82-2-961-2316 (K.S.A.); +65-6516-3267 (G.S.); +1-(941)-782-5950 (A.B.); Fax: +65-6873-7690 (G.S.)
                Author information
                https://orcid.org/0000-0002-2882-0612
                https://orcid.org/0000-0001-9159-960X
                Article
                cancers-11-00611
                10.3390/cancers11050611
                6562434
                31052435
                65ae4ca3-99af-45d4-b91c-9373e5d59a2b
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 March 2019
                : 28 April 2019
                Categories
                Review

                formononetin,cancer,preclinical models,cell signaling,angiogenesis

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