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      Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

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          Abstract

          Cancer is a multistage process resulting in an uncontrolled and abrupt division of cells and is one of the leading causes of mortality. The cases reported and the predictions for the near future are unthinkable. Food and Drug Administration data showed that 40% of the approved molecules are natural compounds or inspired by them, from which, 74% are used in anticancer therapy. In fact, natural products are viewed as more biologically friendly, that is less toxic to normal cells. In this review, the most recent and successful cases of secondary metabolites, including alkaloid, diterpene, triterpene and polyphenolic type compounds, with great anticancer potential are discussed. Focusing on the ones that are in clinical trial development or already used in anticancer therapy, therefore successful cases such as paclitaxel and homoharringtonine (in clinical use), curcumin and ingenol mebutate (in clinical trials) will be addressed. Each compound’s natural source, the most important steps in their discovery, their therapeutic targets, as well as the main structural modifications that can improve anticancer properties will be discussed in order to show the role of plants as a source of effective and safe anticancer drugs.

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          Most cited references127

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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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            Natural products: an evolving role in future drug discovery.

            The therapeutic areas of infectious diseases and oncology have benefited from abundant scaffold diversity in natural products, able to interact with many specific targets within the cell and indeed for many years have been source or inspiration for the majority of FDA approved drugs. The present review describes natural products (NPs), semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration from 2005 to 2010 by disease area i.e. infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases and oncology. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
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              Natural product and natural product derived drugs in clinical trials.

              There are a significant number of natural product (NP) drugs in development. We review the 100 NP and NP-derived compounds and 33 Antibody Drug Conjugates (ADCs) with a NP-derived cytotoxic component being evaluated in clinical trials or in registration at the end of 2013. 38 of these compounds and 33 ADCs are being investigated as potential oncology treatments, 26 as anti-infectives, 19 for the treatment of cardiovascular and metabolic diseases, 11 for inflammatory and related diseases and 6 for neurology. There was a spread of the NP and NP-derived compounds through the different development phases (17 in phase I, 52 in phase II, 23 in phase III and 8 NDA and/or MAA filed), while there were 23 ADCs in phase I and 10 in phase II. 50 of these 100 compounds were either NPs or semi-synthetic (SS) NPs, which indicated the original NP still plays an important role. NP and NP-derived compounds for which clinical trials have been halted or discontinued since 2008 are listed in the Supplementary Information. The 25 NP and NP-derived drugs launched since 2008 are also reviewed, and late stage development candidates and new NP drug pharmacophores analysed. The short term prospect for new NP and NP-derived drug approvals is bright, with 31 compounds in phase III or in registration, which should ensure a steady stream of approvals for at least the next five years. However, there could be future issues for new drug types as only five new drug pharmacophores discovered in the last 15 years are currently being evaluated in clinical trials. The next few years will be critical for NP-driven lead discovery, and a concerted effort is required to identify new biologically active pharmacophores and to progress these and existing compounds through pre-clinical drug development into clinical trials.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                16 January 2018
                January 2018
                : 19
                : 1
                : 263
                Affiliations
                [1 ]cE3c—Centre for Ecology, Evolution and Environmental Changes/Azorean Biodiversity Group & Faculty of Sciences and Technology, University of Azores, Rua Mãe de Deus, 9501-321 Ponta Delgada, Portugal
                [2 ]Department of Chemistry & QOPNA—Organic Chemistry, Natural Products and Food Stuffs, University of Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal; diana@ 123456ua.pt
                Author notes
                [* ]Correspondence: ana.ml.seca@ 123456uac.pt ; Tel.: +351-296-650-172
                Author information
                https://orcid.org/0000-0002-7709-2375
                Article
                ijms-19-00263
                10.3390/ijms19010263
                5796209
                29337925
                2e9a28b3-70a5-4d21-8f23-c1f3b0d37284
                © 2018 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
                : 12 December 2017
                : 12 January 2018
                Categories
                Review

                Molecular biology
                secondary metabolites,clinical trial,anticancer therapy,vincristine,paclitaxel,homoharringtonine,ingenol mebutate,curcumin,betulinic acid

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