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      Endophytic Fungi—Alternative Sources of Cytotoxic Compounds: A Review

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          Abstract

          Cancer is a major cause of death worldwide, with an increasing number of cases being reported annually. The elevated rate of mortality necessitates a global challenge to explore newer sources of anticancer drugs. Recent advancements in cancer treatment involve the discovery and development of new and improved chemotherapeutics derived from natural or synthetic sources. Natural sources offer the potential of finding new structural classes with unique bioactivities for cancer therapy. Endophytic fungi represent a rich source of bioactive metabolites that can be manipulated to produce desirable novel analogs for chemotherapy. This review offers a current and integrative account of clinically used anticancer drugs such as taxol, podophyllotoxin, camptothecin, and vinca alkaloids in terms of their mechanism of action, isolation from endophytic fungi and their characterization, yield obtained, and fungal strain improvement strategies. It also covers recent literature on endophytic fungal metabolites from terrestrial, mangrove, and marine sources as potential anticancer agents and emphasizes the findings for cytotoxic bioactive compounds tested against specific cancer cell lines.

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          Most cited references211

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          Properties of bacterial endophytes and their proposed role in plant growth.

          Bacterial endophytes live inside plants for at least part of their life cycle. Studies of the interaction of endophytes with their host plants and their function within their hosts are important to address the ecological relevance of endophytes. The modulation of ethylene levels in plants by bacterially produced 1-aminocyclopropane-1-carboxylate deaminase is a key trait that enables interference with the physiology of the host plant. Endophytes with this capacity might profit from association with the plant, because colonization is enhanced. In turn, host plants benefit by stress reduction and increased root growth. This mechanism leads to the concept of 'competent' endophytes, defined as endophytes that are equipped with genes important for maintenance of plant-endophyte associations. The ecological role of these endophytes and their relevance for plant growth are discussed here.
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            How Taxol/paclitaxel kills cancer cells

            Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.
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              Drug discovery from medicinal plants.

              Current research in drug discovery from medicinal plants involves a multifaceted approach combining botanical, phytochemical, biological, and molecular techniques. Medicinal plant drug discovery continues to provide new and important leads against various pharmacological targets including cancer, HIV/AIDS, Alzheimer's, malaria, and pain. Several natural product drugs of plant origin have either recently been introduced to the United States market, including arteether, galantamine, nitisinone, and tiotropium, or are currently involved in late-phase clinical trials. As part of our National Cooperative Drug Discovery Group (NCDDG) research project, numerous compounds from tropical rainforest plant species with potential anticancer activity have been identified. Our group has also isolated several compounds, mainly from edible plant species or plants used as dietary supplements, that may act as chemopreventive agents. Although drug discovery from medicinal plants continues to provide an important source of new drug leads, numerous challenges are encountered including the procurement of plant materials, the selection and implementation of appropriate high-throughput screening bioassays, and the scale-up of active compounds.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                26 April 2018
                2018
                : 9
                : 309
                Affiliations
                [1] 1Microbial Metabolite Research Laboratory, Department of Microbiology and Biotechnology, Bangalore University , Bangalore, India
                [2] 2Department of Studies in Molecular Biology, University of Mysore , Mysore, India
                [3] 3Botany and Microbiology Department, College of Science, King Saud University , Riyadh, Saudi Arabia
                [4] 4Department of Studies in Biotechnology, University of Mysore , Mysore, India
                [5] 5Adichunchanagiri Institute for Molecular Medicine, BG Nagara , Mandya, India
                [6] 6Molecular Microbiology and Systematics Laboratory, Department of Biotechnology, Mizoram University , Aizawl, India
                [7] 7Microbiology Division, DRDO-BU-Centre for Life sciences, Bharathiar University , Coimbatore, India
                [8] 8Department of Chemistry and Biotechnology, ERA Chair of Green Chemistry, School of Science, Tallinn University of Technology , Tallinn, Estonia
                [9] 9Plant Production Department, College of Food and Agricultural Sciences, King Saud University , Riyadh, Saudi Arabia
                Author notes

                Edited by: Salvatore Salomone, Università degli Studi di Catania, Italy

                Reviewed by: Gustavo Molina, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Brazil; Marian Brestic, Slovak University of Agriculture, Slovakia

                *Correspondence: Chandra N. Siddaiah moonnayak@ 123456gmail.com

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work.

                Article
                10.3389/fphar.2018.00309
                5932204
                29755344
                d287c8bf-ee52-4162-a1f7-6f1ccdb00998
                Copyright © 2018 Uzma, Mohan, Hashem, Konappa, Rangappa, Kamath, Singh, Mudili, Gupta, Siddaiah, Chowdappa, Alqarawi and Abd_Allah.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 November 2017
                : 16 March 2018
                Page count
                Figures: 27, Tables: 6, Equations: 0, References: 240, Pages: 37, Words: 22445
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                bioactive metabolites,anticancer agents,natural compounds,fungal alkaloids,taxol,podophyllotoxin,camptothecin,vinca alkaloids

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