Phaleria macrocarpa (Boerl.) fruit induce G(0)/G(1) and G(2)/M cell cycle arrest and apoptosis through mitochondria-mediated pathway in MDA-MB-231 human breast cancer cell

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Ethnopharmacological relevance: Phaleria macrocarpa (Scheff) Boerl, is a well-known folk medicinal plant in Indonesia. Traditionally, P. macrocarpa has been used to control cancer, impotency, hemorrhoids, diabetes mellitus, allergies, liver and
  9/29/2017Phaleria macrocarpa (Boerl.) fruit induce G0/G1 and G2/M cell cycle arrest and apoptosis through mitochondria-mediated pathway in MDA-…  A󰁲󰁴󰁩󰁣󰁬󰁥󰁯󰁵󰁴󰁬󰁩󰁮󰁥    Show full outline Highlights  Abstract Graphical abstract Keywords 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Conflict of interest  Authors' contributions  Acknowledgment References F󰁩󰁧󰁵󰁲󰁥󰁳a󰁮󰁤󰁴ab󰁬󰁥󰁳 •••• Journal of Ethnopharmacology Volume 201, 6 April 2017, Pages 42–55 Phaleria macrocarpa  (Boerl.) fruit induce G 0 /G 1  and G 2 /M cellcycle arrest and apoptosis through mitochondria-mediatedpathway in MDA-MB-231 human breast cancer cell Nowroji Kavitha a , Chern Ein Oon a , Yeng Chen b , Jagat R. Kanwar  c , Sreenivasan Sasidharan a, , Show more Highlights The mode of PMEAF-induced cell death and the mechanisms involved wereexamined.PMEAF induced mainly apoptotic death of breast cancer MDA-MB-231 cells.PMEAF induced mitochondrial-mediated and caspase-dependent apoptosis.p53-mediated pathways are involved in PMEAF-mediated apoptosis in the MDA-MB-231 cells.  Abstract Ethnopharmacological relevance Phaleria macrocarpa  (Scheff) Boerl, is a well-known folk medicinal plant in Indonesia.Traditionally, P. macrocarpa  has been used to control cancer, impotency, hemorrhoids,diabetes mellitus, allergies, liver and hearth disease, kidney disorders, blood diseases,acne, stroke, migraine, and various skin diseases. Aim of the studyThe purpose of this study was to determine the in situ cytotoxicity effect P. macrocarpa fruit ethyl acetate fraction (PMEAF) and the underlying molecular mechanism of celldeath.Materials and methodsMDA-MB-231 cells were incubated with PMEAF for 24 h. Cell cycle and viability wereexamined using flow cytometry analysis. Apoptosis was determined using the Annexin Vassay and also by fluorescence microscopy. Apoptosis protein profiling was detected byRayBio® Human Apoptosis Array.ResultsThe AO/PI staining and flow cytometric analysis of MDA-MB-231 cells treated withPMEAF were showed apoptotic cell death. The cell cycle analysis by flow cytometryanalysis revealed that the accumulation of PMEAF treated MDA-MB-231 cells in G 0 /G 1 and G 2 /M-phase of the cell cycle. Moreover, the PMEAF exert cytotoxicity by increasedthe ROS production in MDA-MB-231 cells consistently stimulated the loss of mitochondrial membrane potential (∆ Ψm ) and induced apoptosis cell death by activationof numerous signalling proteins. The results from apoptosis protein profiling arrayevidenced that PMEAF stimulated the expression of 9 pro-apoptotic proteins (Bax, Bid,caspase 3, caspase 8, cytochrome c  , p21, p27, p53 and SMAC) and suppressed the 4anti-apoptotic proteins (Bcl-2, Bcl-w, XIAP and survivin) in MDA-MB-231 cells.  Get rights and content   Search ScienceDirect    Advanced search D󰁯󰁷󰁮󰁬󰁯a󰁤PDF     Export    9/29/2017Phaleria macrocarpa (Boerl.) fruit induce G0/G1 and G2/M cell cycle arrest and apoptosis through mitochondria-mediated pathway in MDA-… Table 1  ADVERTISEMENT  ConclusionThe results indicated that PMEAF treatment induced apoptosis in MDA-MB-231 cellsthrough intrinsic mitochondrial related pathway with the participation of pro and anti-apoptotic proteins, caspases, G 0 /G 1  and G 2 /M-phases cell cycle arrest by p53-mediatedmechanism. Graphical abstractKeywords Cells cycle arrest; Apoptosis; Caspase, p53, cytochrome c 1. Introduction Breast cancer is the second greatest cancer and the fifth main reason for cancer-relateddeaths in females throughout the world. Continued usage of chemotherapeutic treatmentagainst breast cancer is frequently compromised due to the development of resistanceagainst the anticancer drug ( American Cancer Society, 2015 ; Venkatadri et al  ., 2016).Therefore, finding alternative drugs is essential to decrease the death rate related tobreast cancer worldwide. Numerous medicinal plants rich in naturally occurringphytochemicals have been found to possess a cytotoxic effect that induces apoptoticcancer cell death (Banerjee et al., 2016). One such medicinal plant that is known to haveanticancer potential with various pharmacological activities is Phaleria macrocarpa (Scheff) Boerl of the family Thymelaceae. P. macrocarpa.  It grows well in tropical areas,and is commonly identified as ‘God's crown’ or locally known as ‘Mahkota dewa’. Themature tree height generally ranges from 1 m to 18 m. The flowers of P. macrocarpa make a compound of 2–4, and vary in colour from green to maroon. The unripe ellipticalshaped fruit of P. macrocarpa  is green and becomes red upon ripening with a diameter of 3 cm. The seeds of the P. macrocarpa  fruit commonly present as one to two seeds, whichare brown, ovoid and anatropous (  Altaf et al., 2013). The unprocessed usage of this herbhas been reported as poisonous and toxic (Yosie et al., 2011). In Asian folk medicine, P.macrocarpa  has been used to control cancer, impotency, hemorrhoids, diabetes mellitus,allergies, liver and heart diseases, kidney disorders, blood diseases, acne, strokes,migraines, and various skin diseases (  Anggraini and Lewandowsky, 2015). Moreover, P.macrocarpa  is a medicinal plant rich with many phytochemicals and has been broadlystudied for its anticancer activities in multiple cancer cell lines. Even though extensive invitro  anticancer studies have been carried out ( Shwter et al., 2016; Lay et al  ., 2014a ; Lay et al  ., 2014b; Muchtaridi et al., 2014; Riwanto et al., 2011; Tandrasasmita et al., 2010, 2015; Yosie et al., 2011), there have been only limited attempts to explore the cytotoxicity mechanism of the P. macrocarpa  extract in relation to its anticancer activity.With this background, this research was designed to study the in vitro  cytotoxicitymechanism of P. macrocarpa  fruit ethyl acetate fraction (PMEAF) in a breast cancer cellline, MDA-MB-231.The cytotoxicity of anticancer drugs should destroy the cancerous cell without adverseeffects on normal cells, which is possible through the induction of apoptosis(Blagosklonny, 2004). Medicinal plants trigger apoptotic pathways that inhibit cell growththrough various mechanisms in cancer cells (Safarzadeh et al., 2014). Furthermore, acancer cell undergoing apoptosis triggers a series of molecular and biochemical events Figure options  9/29/2017Phaleria macrocarpa (Boerl.) fruit induce G0/G1 and G2/M cell cycle arrest and apoptosis through mitochondria-mediated pathway in MDA-… that lead to unique characteristics that might be determined by microscopy,biochemically, or flow cytometry techniques. The typical morphological features of apoptotic cells can be observed through microscopic studies (Saraste and Pulkki, 2000). A morphological observation study using Acridine Orange/Propidium Iodide (AO/PI)staining with a fluorescence microscope strongly revealed that PMEAF treatmentinduced higher apoptotic cell death in PMEAF treated MDA-MB-231 cells compared tothe non-treated control cells. Moreover, the majority of structural and biochemical eventshappening during cell death can be examined by flow cytometry. Therefore, it is importantto further study the molecular mechanism of PMEAF apoptotic cell death activitiesagainst MDA-MB-231 cells. Hence, the current study was conducted to providebiochemical evidence concerning the apoptotic cell death activities of PMEAF in detail bymulti-parametric flow cytometric analysis and biochemical assay of the functional eventsassociated with cell apoptosis. The molecular mechanism of PMEAF responsible for such apoptotic cell death activities plays a significant role in determining the efficacy of specific treatments that lead to efficient cancer cell death (Hassan et al., 2014). R󰁥󰁣󰁯󰁭󰁭󰁥󰁮󰁤󰁥󰁤a󰁲󰁴󰁩󰁣󰁬󰁥󰁳    I󰁮󰁳󰁩󰁴󰁵     󰁭󰁯󰁲󰁰󰁨󰁯󰁬󰁯󰁧󰁩󰁣a󰁬a󰁳󰁳󰁥󰁳󰁳󰁭󰁥󰁮󰁴󰁯󰁦a󰁰󰁯󰁰󰁴󰁯󰁳󰁩󰁳󰁩󰁮󰁤󰁵    …                                       P󰁯󰁬󰁹󰁡󰁬󰁴󰁨󰁩󰁡󰁬󰁯󰁮󰁧󰁩󰁦󰁯󰁬󰁩󰁡     M󰁥󰁴󰁨a󰁮󰁯󰁬󰁩󰁣L󰁥a󰁦E󰁸󰁴󰁲a󰁣󰁴󰁳(PLM      …                                       Ka󰁩X󰁩󰁮Sa󰁮a󰁱󰁵󰁥󰁯󰁵󰁳󰁥󰁸󰁴󰁲a󰁣󰁴󰁩󰁭󰁰󰁲󰁯󰁶󰁥󰁳A     β    1-40 -󰁩󰁮󰁤󰁵󰁣    …                                       View more articles » 2017, Biomedicine & Pharmacotherapy more 2017, Biomedicine & Pharmacotherapy more 2017, Journal of Ethnopharmacology more C󰁩󰁴󰁩󰁮󰁧a󰁲󰁴󰁩󰁣󰁬󰁥󰁳(2)  R󰁥󰁬a󰁴󰁥󰁤b󰁯󰁯󰁫󰁣󰁯󰁮󰁴󰁥󰁮󰁴  
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