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      Mesua ferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways

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          Abstract

          Considering the great potential of natural products as anticancer agents, the present study was designed to explore the molecular mechanisms responsible for anticancer activities of Mesua ferrea stem bark extract against human colorectal carcinoma. Based on MTT assay results, bioactive sub-fraction (SF-3) was selected for further studies using HCT 116 cells. Repeated column chromatography resulted in isolation of less active α-amyrin from SF-3, which was identified and characterized by GC-MS and HPLC methods. α-amyrin and betulinic acid contents of SF-3 were measured by HPLC methods. Fluorescent assays revealed characteristic apoptotic features, including cell shrinkage, nuclear condensation, and marked decrease in mitochondrial membrane potential in SF-3 treated cells. In addition, increased levels of caspases-9 and -3/7 levels were also observed in SF-3 treated cells. SF-3 showed promising antimetastatic properties in multiple in vitro assays. Multi-pathway analysis revealed significant down-regulation of WNT, HIF-1α, and EGFR with simultaneous up-regulation of p53, Myc/Max, and TGF-β signalling pathways in SF-3 treated cells. In addition, promising growth inhibitory effects were observed in SF-3 treated HCT 116 tumour spheroids, which give a hint about in vivo antitumor efficacy of SF-3 phytoconstituents. In conclusion, these results demonstrated that anticancer effects of SF-3 towards colon cancer are through modulation of multiple molecular pathways.

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          Most cited references 19

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          Polypharmacology: challenges and opportunities in drug discovery.

          At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this review, we will compare advantages and disadvantages of multitarget versus combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multitarget drugs.
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            Myc pathways provoking cell suicide and cancer.

            A paradox for the cancer biology field has been the revelation that oncogenes, once thought to simply provide advantages to a cancer cell, actually put it at dire risk of cell suicide. Myc is the quintessential oncogene in this respect, as in normal cells it is required for cell cycle traverse, whereas in cancers it is overexpressed and functions as the angiogenic switch. Nonetheless, Myc overexpression kills normal cells dead in their tracks. Here we review Myc-induced pathways that contribute to the apoptotic response. Molecular analysis of Myc-induced tumors has established that some of these apoptotic pathways are essential checkpoints that guard the cell from cancer, as they are selectively bypassed during tumorigenesis. The precise mechanism(s) by which Myc targets these pathways are largely unresolved, but we propose that they involve crosstalk and feedback regulatory loops between arbiters of cell death.
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              Natural products for cancer prevention: a global perspective.

              The control of cancer, the second leading cause of death worldwide, may benefit from the potential that resides in alternative therapies. The primary carcinogens stem from a variety of agricultural, industrial, and dietary factors. Conventional therapies cause serious side effects and, at best, merely extend the patient's lifespan by a few years. There is thus the need to utilise alternative concepts or approaches to the prevention of cancer. This review focuses on the many natural products that have been implicated in cancer prevention and that promote human health without recognisable side effects. These molecules originate from vegetables, fruits, plant extracts, and herbs.
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                Author and article information

                Journal
                CJNM
                Chinese Journal of Natural Medicines
                Elsevier
                1875-5364
                20 July 2017
                : 15
                : 7
                : 505-514
                Affiliations
                1EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia
                2Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia
                3Department of Pharmacology, School of Medical Sciences, Quest International University, Perak, Malaysia
                4Centre for Drug Research, Universiti Sains Malaysia, Penang, 11800, Malaysia
                5Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia
                Author notes
                *Corresponding author: Muhammad Asif, E-mail: asif_pharmacist45@ 123456yahoo.com ; Amin Malik Shah Abdul Majid, E-mail: Aminmalikshah@ 123456gmail.com .

                These authors have no conflict of interest to declare.

                Article
                S1875-5364(17)30076-6
                10.1016/S1875-5364(17)30076-6
                Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
                Funding
                Funded by: Universti Sains Malaysia
                Award ID: RUT 1001/PFARMASI/851001 NRGS 304/PFARMASI/650735/K123
                This work was supported by the fund from Universti Sains Malaysia (RUT 1001/PFARMASI/851001 NRGS 304/PFARMASI/650735/K123).

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