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      Subchronic toxicity, immunoregulation and anti-breast tumor effect of Nordamnacantal, an anthraquinone extracted from the stems of Morinda citrifolia L

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          Abstract

          Background

          Morinda citrifolia L. that was reported with immunomodulating and cytotoxic effects has been traditionally used to treat multiple illnesses including cancer. An anthraquinone derived from fruits of Morinda citrifolia L., nordamnacanthal, is a promising agent possessing several in vitro biological activities. However, the in vivo anti-tumor effects and the safety profile of nordamnacanthal are yet to be evaluated.

          Methods

          In vitro cytotoxicity of nordamnacanthal was tested using MTT, cell cycle and Annexin V/PI assays on human MCF-7 and MDA-MB231 breast cancer cells. Mice were orally fed with nordamnacanthal daily for 28 days for oral subchronic toxicity study. Then, the in vivo anti-tumor effect was evaluated on 4T1 murine cancer cells-challenged mice. Changes of tumor size and immune parameters were evaluated on the untreated and nordamnacanthal treated mice.

          Results

          Nordamnacanthal was found to possess cytotoxic effects on MDA-MB231, MCF-7 and 4T1 cells in vitro. Moreover, based on the cell cycle and Annexin V results, nordamnacanthal managed to induce cell death in both MDA-MB231 and MCF-7 cells. Additionally, no mortality, signs of toxicity and changes of serum liver profile were observed in nordamnacanthal treated mice in the subchronic toxicity study. Furthermore, 50 mg/kg body weight of nordamncanthal successfully delayed the progression of 4T1 tumors in Balb/C mice after 28 days of treatment. Treatment with nordamnacanthal was also able to increase tumor immunity as evidenced by the immunophenotyping of the spleen and YAC-1 cytotoxicity assays.

          Conclusion

          Nordamnacanthal managed to inhibit the growth and induce cell death in MDA-MB231 and MCF-7 cell lines in vitro and cease the tumor progression of 4T1 cells in vivo . Overall, nordamnacanthal holds interesting anti-cancer properties that can be further explored.

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          Most cited references28

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          Targeting natural killer cells and natural killer T cells in cancer.

          Natural killer (NK) cells and natural killer T (NKT) cells are subsets of lymphocytes that share some phenotypical and functional similarities. Both cell types can rapidly respond to the presence of tumour cells and participate in antitumour immune responses. This has prompted interest in the development of innovative cancer therapies that are based on the manipulation of NK and NKT cells. Recent studies have highlighted how the immune reactivity of NK and NKT cells is shaped by the environment in which they develop. The rational use of these cells in cancer immunotherapies awaits a better understanding of their effector functions, migratory patterns and survival properties in humans.
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            Natural products in drug discovery and development.

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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

                Contributors
                nadyaboo@gmail.com
                rizieaq@gmail.com
                skyeap2005@gmail.com
                noraininordin1303@gmail.com
                elyani.mohamad@gmail.com
                pidut232@yahoo.com
                edayahchem87@gmail.com
                drstamilselvan@gmail.com
                norhadiani@salam.uitm.edu.my
                noorjahan@upm.edu.my
                Journal
                BMC Complement Altern Med
                BMC Complement Altern Med
                BMC Complementary and Alternative Medicine
                BioMed Central (London )
                1472-6882
                27 January 2018
                27 January 2018
                2018
                : 18
                : 31
                Affiliations
                [1 ]ISNI 0000 0004 0627 933X, GRID grid.240541.6, UKM Molecular Biology Institute (UMBI), UKM Medical Center, ; Jalan Yaacob Latif, Bandar Tun Razak 56000 Cheras, Kuala Lumpur, Malaysia
                [2 ]ISNI 0000 0001 2231 800X, GRID grid.11142.37, Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, , Universiti Putra Malaysia, ; 43400 Serdang, Malaysia
                [3 ]China-ASEAN College of Marine Sciences, Xiamen University Malaysia, 43900 Sepang, Selangor Malaysia
                [4 ]ISNI 0000 0001 2161 1343, GRID grid.412259.9, Atta-ur-Rahman Institute for Natural Products Discovery, , Universiti Teknologi MARA, ; 40450 Puncak Alam, Selangor Malaysia
                Author information
                http://orcid.org/0000-0003-1966-8580
                Article
                2102
                10.1186/s12906-018-2102-3
                5787285
                29374471
                55b88d2c-4da3-4220-9422-6812ee06ee2f
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 July 2017
                : 17 January 2018
                Funding
                Funded by: Chemical Marker Project, NRGS scheme
                Award ID: NRGS scheme
                Award Recipient :
                Funded by: Putra Grant Scheme from the Universiti Putra Malaysia.
                Award ID: (GP-IPB/2013/9412802)
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Complementary & Alternative medicine
                nordamnacanthal,morinda citrifolia,breast cancer,4t1,immunomodulation

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