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      • Record: found
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      Eriodictyol exerts potent anticancer activity against A549 human lung cancer cell line by inducing mitochondrial-mediated apoptosis, G2/M cell cycle arrest and inhibition of m-TOR/PI3K/Akt signalling pathway

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          Abstract

          Introduction

          Eriodictyol is an important flavonoid and is commonly present across the plant kingdom. Flavonoids have been reported to show incredible pharmacological potential. However, the anticancer activity of the important flavonoid eriodictyol has not been well reported. In the present study we determined its anticancer potential against the human lung cancer cell line A549.

          Material and methods

          The initial cytotoxicity induced by eriodictyol was measured by MTT assay. Flow cytometry was used to study the effects of eriodictyol on apoptosis, cell cycle phase distribution and mitochondrial membrane potential loss. The comet assay was used to measure DNA damage induced by eriodictyol in cancer cells while the western blot assay indicated effects of the compound on Bax/Blc-2 and PI3K/AKT/m-TOR proteins.

          Results

          The results showed that eriodictyol has an IC 50 value of 50 μM against human lung cancer cells as compared to the IC 50 of 95 µM against non-cancerous FR2 cells. The molecule exerted its anticancer activity through induction of apoptosis by regulating the Bcl-2/Bax signalling pathway. It caused cell cycle arrest of human lung cancer A549 cells at G2/M phase. Eriodictyol was also found to cause a reduction of the mitochondrial membrane potential in a dose-dependent manner. Additionally, eriodictyol effectively inhibited the mTOR/PI3K/Akt signalling pathway in a dose-dependent manner.

          Conclusions

          Based on the above findings, we conclude that eriodictyol exerts its anticancer activity through induction of mitochondrial apoptosis and G2/M cell cycle arrest and inhibition of the TOR/PI3K/Akt cascade, indicating that it may have potential as a lead compound in the treatment of lung cancer, provided further in depth studies are done.

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          Most cited references18

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          Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario.

          D. Green, Jerry E Chipuk, Erin L Hayes (2006)
          Mitochondrial outer membrane permeabilization (MOMP) is considered the 'point of no return' as this event is responsible for engaging the apoptotic cascade in numerous cell death pathways. MOMP is directly governed by a subset of the BCL-2 family of proapoptotic proteins, which induce disruptions in the outer mitochondrial membrane (OMM) and subsequent release of death-promoting proteins like cytochrome c. The proposal here is centered on our hypothesis that MOMP is dictated by an interaction between the cytosol and the OMM, and although proteins of the OMM may be important in the process, the 'decision' to undergo apoptosis originates within the cytosol with no participation (in terms of yes, no and when) by mitochondria.
          Article 0 comments Cited 138 times – based on 0 reviews     Review now
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            Apoptosis as a novel target for cancer chemoprevention.

            Numsen Hail Jr., Reuben Lotan, Shi-yong R Sun (2004)
            Cancer chemopreventive agents are typically natural products or their synthetic analogs that inhibit the transformation of normal cells to premalignant cells or the progression of premalignant cells to malignant cells. These agents are believed to function by modulating processes associated with xenobiotic biotransformation, with the protection of cellular elements from oxidative damage, or with the promotion of a more differentiated phenotype in target cells. However, an increasing number of chemopreventive agents (e.g., certain retinoids, nonsteroidal anti-inflammatory drugs, polyphenols, and vanilloids) have been shown to stimulate apoptosis in premalignant and malignant cells in vitro or in vivo. Apoptosis is arguably the most potent defense against cancer because it is the mechanism used by metazoans to eliminate deleterious cells. Many chemopreventive agents appear to target signaling intermediates in apoptosis-inducing pathways. Inherently, the process of carcinogenesis selects against apoptosis to initiate, promote, and perpetuate the malignant phenotype. Thus, targeting apoptosis pathways in premalignant cells--in which these pathways are still relatively intact--may be an effective method of cancer prevention. In this review, we construct a paradigm supporting apoptosis as a novel target for cancer chemoprevention by highlighting recent studies of several chemopreventive agents that engage apoptosis pathways.
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              Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action.

              M Abal, J. Andreu, I Barasoain (2003)
              Microtubules are highly dynamic cellular polymers made of alphabeta-tubulin and associated proteins. They play a key role during mitosis, participating in the exact organization and function of the spindle, and are critical for assuring the integrity of the segregated DNA. Therefore, they represent one of the more effective targets in current cancer therapy. Paclitaxel (Taxol) is the prototype of the taxane family of antitumor drugs, and it was the first natural product shown to stabilize microtubules. This unique mechanism of action is in contrast to other microtubule poisons, such as Vinca alkaloids, colchicine, and cryptophycines, which inhibit tubulin polymerization. Taxanes block cell cycle progression through centrosomal impairment, induction of abnormal spindles and suppression of spindle microtubule dynamics. Triggering of apoptosis by aberrant mitosis or by subsequent multinucleated G1-like state related to mitotic slippage, depends on cell type and drug schedule. The development of fluorescent derivatives of paclitaxel led us to locate spindle pole microtubules and centrosomes as main sub-cellular targets of cytotoxic taxoids in living cells. In this review we discuss these findings in the context of a cell cycle-dependent response to taxanes, based on the cellular targets, and the status of the implicated cell cycle checkpoints. We also review those events that can influence this response, like the different signal transduction pathways activated/inactivated in relation to Bcl-2 phosphorylation and induction of apoptosis, and the controversial role of the p53 status on cell sensitivity to paclitaxel. Finally, cell cycle-dependent resistance, an emerging concept in combination sequential chemotherapy, is discussed on the basis of the cell cycle-dependent mechanisms of action of taxanes.
              Article 0 comments Cited 93 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Arch Med Sci
                Journal ID (iso-abbrev): Arch Med Sci
                Journal ID (publisher-id): AMS
                Title: Archives of Medical Science : AMS
                Publisher: Termedia Publishing House
                ISSN (Print): 1734-1922
                ISSN (Electronic): 1896-9151
                Publication date (Electronic): 17 May 2019
                Publication date Collection: 2020
                Volume: 16
                Issue: 2
                Pages: 446-452
                Affiliations
                [1 ]Department of Respiratory Medicine, The Affiliated Hospital of Panzhihua University, Panzhihua, China
                [2 ]Department of Respiratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
                [3 ]Department of Emergency, The Affiliated Hospital of Panzhihua University, Panzhihua, China
                Author notes
                Corresponding author: Yong Zhang, Department of Respiratory Medicine, The Affiliated Hospital of Panzhihua University, Panzhihua, 617000, China. Phone/fax: +86 0812 2213492. E-mail: yongzhang33@ 123456hotmail.com
                Article
                Publisher ID: 36693
                DOI: 10.5114/aoms.2019.85152
                PMC ID: 7069446
                PubMed ID: 32190156
                SO-VID: 0a212cca-e725-4e2f-b63c-0a265890aea5
                Copyright © Copyright: © 2019 Termedia & Banach
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

                History
                Date received : 28 April 2017
                Date accepted : 07 July 2017
                Categories
                Subject: Basic Research

                ScienceOpen disciplines: Medicine
                Keywords: lung cancer,eriodictyol,apoptosis,cell cycle arrest,flow cytometer
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: lung cancer, eriodictyol, apoptosis, cell cycle arrest, flow cytometer

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