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      Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems

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          Abstract

          Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.

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          Drug-like properties and the causes of poor solubility and poor permeability

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            Luteolin, a flavonoid with potential for cancer prevention and therapy.

            Luteolin, 3',4',5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3'-kinase (PI3K)/Akt, nuclear factor kappa B (NF-kappaB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin.
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              Drug-like properties and the causes of poor solubility and poor permeability.

              C Lipinski (2001)
              There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.
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                Author and article information

                Journal
                J Oncol
                J Oncol
                JO
                Journal of Oncology
                Hindawi
                1687-8450
                1687-8469
                2017
                7 May 2017
                : 2017
                : 7351976
                Affiliations
                1Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
                2Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
                Author notes
                *Ana Ramírez de Molina: ana.ramirez@ 123456imdea.org

                Academic Editor: Akira Hara

                Author information
                http://orcid.org/0000-0002-2090-4045
                http://orcid.org/0000-0002-6284-3236
                http://orcid.org/0000-0003-1439-7494
                Article
                10.1155/2017/7351976
                5438845
                db73eb23-8796-4bb6-9e41-47bfe93abcbc
                Copyright © 2017 Lamia Mouhid et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 December 2016
                : 6 March 2017
                Funding
                Funded by: Ministerio de Economía y Competitividad
                Award ID: AGL2013-48943-C2-2-R
                Funded by: Gobierno Regional de la Comunidad de Madrid
                Award ID: P2013/ABI-2728
                Funded by: EU Structural Funds
                Categories
                Review Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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