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      Berberine, an Epiphany Against Cancer

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          Abstract

          Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated.

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          Berberine: new perspectives for old remedies.

          Micol Tillhon, Luis M. Guamán Ortiz, Paolo Lombardi … (2012)
          Chemical compounds derived from plants have been used since the origin of human beings to counteract a number of diseases. Among them, the natural isoquinoline alkaloid berberine has been employed in Ayurvedic and Chinese Medicine for hundreds of years with a wide range of pharmacological and biochemical effects. More recently, a growing body of reports supports the evidence that berberine has anticancer effects, being able to block the proliferation of and to kill cancer cells. This review addresses the properties and therapeutic use of berberine and focuses on the recent advances as promising anticancer drug lead. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The catalytic mechanism and structure of thymidylate synthase.

            María Carreras, D Santi (1994)
            Thymidylate synthase (TS, EC 2.1.1.45) catalyzes the reductive methylation of dUMP by CH2H4folate to produce dTMP and H2folate. Knowledge of the catalytic mechanism and structure of TS has increased substantially over recent years. Major advances were derived from crystal structures of TS bound to various ligands, the ability to overexpress TS in heterologous hosts, and the numerous mutants that have been prepared and analyzed. These advances, coupled with previous knowledge, have culminated in an in-depth understanding of many important molecular details of the reaction. We review aspects of TS catalysis that are most pertinent to understanding the current status of the structure and catalytic mechanism of the enzyme. Included is a discussion of available sources and assays for TS, a description of the enzyme's chemical mechanism and crystal structure, and a summary of data obtained from mutagenesis experiments.
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              Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells.

              Santosh Katiyar, Sudheer K. Mantena, S. Sharma (2006)
              Berberine, a naturally occurring isoquinoline alkaloid, has been shown to possess anti-inflammatory and antitumor properties in some in vitro systems. Here, we report that in vitro treatment of androgen-insensitive (DU145 and PC-3) and androgen-sensitive (LNCaP) prostate cancer cells with berberine inhibited cell proliferation and induced cell death in a dose-dependent (10-100 micromol/L) and time-dependent (24-72 hours) manner. Treatment of nonneoplastic human prostate epithelial cells (PWR-1E) with berberine under identical conditions did not significantly affect their viability. The berberine-induced inhibition of proliferation of DU145, PC-3, and LNCaP cells was associated with G1-phase arrest, which in DU145 cells was associated with inhibition of expression of cyclins D1, D2, and E and cyclin-dependent kinase (Cdk) 2, Cdk4, and Cdk6 proteins, increased expression of the Cdk inhibitory proteins (Cip1/p21 and Kip1/p27), and enhanced binding of Cdk inhibitors to Cdk. Berberine also significantly (P < 0.05-0.001) enhanced apoptosis of DU145 and LNCaP cells with induction of a higher ratio of Bax/Bcl-2 proteins, disruption of mitochondrial membrane potential, and activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase. Pretreatment with the pan-caspase inhibitor z-VAD-fmk partially, but significantly, blocked the berberine-induced apoptosis, as also confirmed by the comet assay analysis of DNA fragmentation, suggesting that berberine-induced apoptosis of human prostate cancer cells is mediated primarily through the caspase-dependent pathway. The effectiveness of berberine in checking the growth of androgen-insensitive, as well as androgen-sensitive, prostate cancer cells without affecting the growth of normal prostate epithelial cells indicates that it may be a promising candidate for prostate cancer therapy.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 15 August 2014
                Publication date Collection: August 2014
                Volume: 19
                Issue: 8
                Pages: 12349-12367
                Affiliations
                [1 ]Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, Pavia 27100, Italy; E-Mail: tillhon@ 123456igm.cnr.it
                [2 ]Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, San Cayetano Alto, Calle París, Loja 1101608, Ecuador; E-Mail: lmguaman@ 123456utpl.edu.ec
                [3 ]Naxospharma, Via Giuseppe di Vittorio 70, Novate Milanese 20026, Italy; E-Mail: p.lombardi@ 123456naxospharma.eu
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: scovassi@ 123456igm.cnr.it ; Tel.: +39-0382-546-334; Fax: +39-0382-422-286.
                Article
                Publisher ID: molecules-19-12349
                DOI: 10.3390/molecules190812349
                PMC ID: 6271598
                PubMed ID: 25153862
                SO-VID: a2098aa4-2240-47af-85e7-3aa1786b0c1a
                Copyright © © 2014 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 27 June 2014
                Date revision received : 06 August 2014
                Date accepted : 11 August 2014
                Categories
                Subject: Review

                Keywords: apoptosis,autophagy,berberine,cancer,traditional medicine
                Data availability:
                Keywords: apoptosis, autophagy, berberine, cancer, traditional medicine

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