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��ࡱ�>��	JL����GHI�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	��5kbjbj����	qvΐΐ�C�������BB�����$�������P��T��VQi� � � �U�U�U�U�U�U�U$�X��[:�U��� � � � � �U���V~E~E~E� � ���U~E� �U~E~ErXNTXO��������nA�N�U�V0�V�N��[vC�[XOXO��[��O�� � ~E� � � � � �U�U~E� � � �V� � � � ���������������������������������������������������������������������[� � � � � � � � � B	K:	 Curcumin Reduced Gold Nanoparticles Induces Reactive Oxygen Species Mediated Apoptosis in MCF-7 Cancer Cells K. Sindhua*, R. Rajarama and A. Rajaramb
aBiochemistry laboratory, Central Leather Research Institute, Adyar, Chennai, India, 600020.
bBiophysics laboratory, Central Leather Research Institute, Adyar, Chennai, India, 600020.


					




*Corresponding author:
Dr. (Mrs.) K. Sindhu
Biochemistry Laboratory
Central Leather Research Institute
Adyar, Chennai -600020, India.
Mob: +91 9495577928
Email:  HYPERLINK "mailto:sindukondath@gmail.com" sindukondath@gmail.com
Abstract
Nanoformulations of curcumin, specifically with gold nanoparticles,�are well set to overcome its bane of poor bioavailability. But their synthesis methodology involving the utilization of many external chemicals can produce adverse side effects further�limiting their exploitation. We have tried to solve this problem in our previous study by synthesizing stable, uniform and biocompatible AuNPs using curcumin alone (cAuNPs) as the reducing and stabilizing agent. Now, we provide evidences for a synergistic effect by gold core and curcumin against breast cancer cells MCF-7. cAuNPs are found to interact with proteins in the biological media to form a corona which might aid in their endocytosis as visualized through electron microscopy. Inside the cells, cAuNPs triggers the generation of reactive oxygen species which then depletes mitochondrial membrane potential. As a consequence apoptotic protein Bax is released that activates different processes such as PARP cleavage and DNA fragmentation. The final stages of apoptosis including chromatin condensation and loss of filopodia are visualized through microscopy. Ultramicroscopic and flow cytometric studies confirm apoptotic mode of cell death. These findings provide insights in to the mechanism of action of cAuNPs in inducing apoptosis and also�suggest their promising candidature as a chemotherapeutic drug.
Key words: Curcumin, gold nanoparticles, breast cancer, protein corona, apoptosis, ROS, synergistic effect, MCF-7 cells
Introduction
Cancer is one of the leading causes of death with 9.6 million deaths reported in 2018. Out of this, about 626679 deaths are caused due to breast cancer. Breast cancer represents 25% of total cancer cases with high mortality.  Their incidence rate is rapidly increasing in both developed and developing countries. The incidence rate in India is predicted to go as high as 1797900 by 2020 [1-4]. Although chemotherapy is the successful and most widely used treatment strategy, resistance, recurrence, non-specific targeting and adverse side effects produced are its limitations [5]. These limitations primarily arise from poor bioavailability of the chemotherapeutic agents and are being addressed to an extent through drug delivery vehicles [6]. Phytochemicals are the prominently used chemotherapeutic agents which inhibit the function of fast growing cells by inducing apoptosis [7]. 
Curcumin is one such phytochemical (a polyphenol) whose poor bioavailability limits the exploitation of its numerous therapeutic activities.  Extensive research on this molecule reveals its plethora of biological activities such as anti-oxidant, anti-proliferative, anti-inflammatory etc. [8, 9]. By inducing apoptosis through multiple signaling pathways it can inhibit different levels of cell signaling mechanisms [10, 11]. The limitation of such an ideal chemotherapeutic agent is being overcome through numerous methods including the revolutionary technology of nanoscience, latest in the field.  A variety of nanoformulations of curcumin have been made such as nano emulsions, liposomes, dendrimers, solid lipid particles, conjugation with magnetic and metal nanoparticles (NPs) etc. [12].  
Out of metal NPs, gold NPs (AuNPs) are one of the flexible, reliable and most prominent NPs being used for cancer therapy. They have a wide range of application in both diagnostic and therapeutic functions [13]. Conjugations of curcumin with AuNPs which show anti-cancer activities have been reported [14-17]. Treament of HeLa, Glioma and Caco-2 cells with AuNPs reduced by hyaluronic acid solubilised curcumin, show high anti-cancer properties when compared with free curcumin [14]. Curcumin conjugated polyvinyl pyrrolidone (PVP) capped citrate reduced AuNPs are also found to be toxic towards TZM-b1 cells (a HeLa cell line derivative) [15]. Protein polymer AuNP nanocomposites show high curcumin loading capacity and enhanced uptake into MCF-7 breast cancer cells [14]. Alginate curcumin reduced AuNPs conjugated to methotrexate has been reported to get easily internalized in MCF-7 and induce apoptosis [17]. These results points out to the good anti-cancer activity of curcumin conjugated AuNPs. But in all the above reports, either external chemicals are used for solubilizing curcumin which is then used to synthesize AuNPs or curcumin is conjugated to previously synthesized AuNPs. Besides, other chemotherapeutic agents have also been used to bring about anti-cancer activity.
Albeit the final aim, when included in nanotechnology for cancer therapy is to synthesize an efficient formulation, which can not only cause toxicity but also show a superior activity when compared to the native compound, it should also adhere to green technology. This advocates the production of nanoformulation which uses very less number of reactants in order to minimize the side effects [18]. We have previously reported the synthesis of stable and biocompatible AuNPs with curcumin alone (cAuNPs) as the reducing and stabilizing agent [19]. Because curcumin is well known for its anti-carcinogenicity by inducing apoptosis, these cAuNPs have been analysed for their efficacy against breast cancer cells MCF-7. We have conducted experiments to find out whether they retain the beneficial properties of curcumin and also if any synergistic effect is produced when in conjugation with AuNPs. We have also tried to dissect the mechanism of their action in inducing apoptosis.
Materials and Methods
Materials
Gold (III) chloride hydrate (HAuCl4) 99.99% pure, BSA, dimethylsulphoxide (DMSO) Dulbecco�s minimum essential medium (DMEM), pencillin, streptomycin, gentamycin, amphotericin B, resazurin (Alamar Blue), ethidium bromide (EtBr),  acridine orange (AO),  4�-6-diamidino-2-phenylindole (DAPI), Propidium Iodide (PI), ribonuclease A (RNase A), 2�,7�-dichlorodihydrofluorescin (DCFH-DA), proteinase K, 5,5�,6,6�-tetrachloro-1,1�,3,3� tetraethylbenzimidazolylcarbocyanine (JC-1), TritonX-100, Tween-20, sodium orthovanadate, Ponceau S, ammonium acetate, Nonidet P-40 (NP-40), sodium deoxycholate, phenylmethylsulfonyl fluoride (PMSF), aprotinin, leupeptin, pepstatin, hexamethyldisilazine (HMS), ethylenediaminetetraaceticacid (EDTA) and agarose were purchased from Sigma-Aldrich, USA. Curcumin (1, 7-bis (4 hydroxy, 3methoxy phenyl) hepta 1, 6 diene 3, 5, dione) 98.5% pure was obtained from Alexis Biochemicals, USA. Potassium carbonate (K2CO3) was purchased from Merck, USA. Fetal Bovine Serum (FBS) of U.S. origin was bought from Gibco, USA. Trypsin-EDTA was purchased from Himedia, India. Glutaraldehyde, osmium tetroxide, sodium cacodylate, propylene oxide, Epon 812 resin kit, uranyl acetate, lead citrate and all other reagents for electron microscopy were from EM Sciences, USA. Cyquant NF� Cell proliferation kit was bought from Invitrogen (USA). Annexin V- fluorescein isothiocyanate (FITC) apoptosis detection kit was purchased from BD biosciences, USA. Mouse monoclonal antibodies Bax, Bcl-2 and IgG-HRP conjugated anti-mouse secondary antibody were from Santa Cruz Biotechnology, USA. Anti-human PARP-1 anti-mouse monoclonal antibody was purchased from BD Pharmingen (USA). Anti-mouse monoclonal �-actin was bought from Sigma Chemicals (USA). ECL Western Blotting substrate (Pierce) was from Thermo Fisher Scientific, USA.
Interaction of protein with cAuNPs
The interaction of cAuNPs with proteins was tested using BSA (1M) taken as a standard protein. cAuNPs (10, 23, 45 and 90 �g/ml)  were suspended in BSA (final concentration ranging from 1 X 10-6 M to 10-3 M) for 24 h. After incubation, the mixture was washed by centrifuging at 15000 X g for 3 min. The pellet was suspended in PBS (10 mM phosphate, 150 mM NaCl, 1 mM EDTA, pH 7.5). This step was repeated thrice and the final pellet suspended in 1 ml PBS. For fluorescence measurements, spectra were taken at a range of 300-500 nm with PBS as emission blank. All absorption and fluorescence spectroscopic measurements were made in a multi-mode plate reader (Tecan Infinite M200). The changes in emission peak was analysed by FL/FR ratio which is 20 nm to the left and right respectively from the peak of the spectrum. The values obtained are analysed by the Stern-Volmer equation

where Fo and F are the initial and final fluorescence intensities respectively, Kq is the quenching rate constant, Ksv is Stern-Volmer dynamic quenching constant, �0 is the lifetime of fluorophore in the absence of quenchers and, [AuNPs] their concentration. The number of binding sites can be calculated by the equation

The synthesized cAuNPs were incubated in cell culture media (DMEM with 10% FBS) at above mentioned concentrations for 24 h. After washing, as given above, the samples were subjected to fluorescence measurements.
For visualizing the formation of protein corona, transmission electron microscopy (TEM) analysis was done. The incubated cAuNPs were drop coated onto copper grids and negatively stained with 2% phosophotungstic acid for 20 min. The sample was dried and then viewed through JEOL JEM 1400 instrument operating at 80kV.
Cell culture
Both MCF-7 and HBL-100 cells were cultured in DMEM medium containing 10% FBS, and antibiotics - pencillin (100IU/mL), streptomycin (100�g/mL), gentamicin (30�g/mL), and amphotericin B (2.5�g/mL). The cells were maintained in a CO2 incubator (Binder, Germany) at 5% CO2 and 37�C. Upon reaching 80% confluence, the cells were trypsinised and seeded in cell culture plates for the experiments. The seeded cells were allowed to attach and spread overnight and then treated. HBL-100 cells were used only for biocompatibility study by Alamar blue assay.  
Cell viability and proliferation
For cell viability studies alamar blue assay was conducted. About 20 X 103 cells (MCF-7 and HBL-100) were seeded into a 48 well plate, treated with the three concentrations of cAuNPs (23, 45 and 90 �g/ml) and incubated for 24, 48 and 72 h. For measuring the toxicity induced by curcumin alone present in the cAuNPs, the percentage of curcumin in cAuNPs was calculated from TGA results (performed in our previous study [19]). Accordingly, about 1.75, 3.5 and 7 �g/ml of curcumin in water (from 20 mM curcumin stock solution in DMSO) was used to treat MCF-7 cells for different time periods. 10 �g of resazurin in PBS was added to each well before 6 h of incubation period. The fluorescence of the supernatant was measured (Ex 530 nm and Em 590 nm) and percentage viability calculated with respect to control.
Cyquant cell proliferation assay was conducted according to the manufacturer�s protocol. Briefly a 1X solution of Component A - dye solution was prepared using HBSS. The cells after treatment with cAuNPs and incubation for different time periods as mentioned above were washed with PBS. To this, 30 �l of dye solution was added and incubated for 30 min. After washing off the dye the cells were trypsinised, resuspended in 200 �l of PBS and fluorescence measurements recorded (Ex: 485 nm, Em: 530 nm).
Microscopic studies
50 X 103 cells were grown on glass cover slips and then incubated with cAuNPs (23, 45 and 90 �g/ml) for 24 and 48 h. Live cells were directly imaged using inverted phase contrast Nikon eclipse 200 microscope. For fluorescence microscopy 0.25 �g of each, EtBr and AO in PBS were added to cells after treatment period. The fluorescence emitted was observed by Nikon Eclipse E600 confocal laser scanning microscope C1 (Ex 490 nm). Images were captured using EZ-C1 software. 
Chromatin condensation was visualized by DAPI staining. Cells were grown on coverslips and treated with IC50 concentration of cAuNPs for 48 h. After incubation period, cells were washed with PBS, fixed with 3% paraformaldehyde, permeabilized with 0.1% Triton X-100 and treated with 0.5 �g/mL of DAPI for 10 min. The cells were then observed in an inverted microscope, Euromax, Holland (Ex: 350, 340 nm, and Em: 470, 453 nm).  
Ultra structural studies 
The morphological features of cells were observed in detail through electron microscopy after treatment with IC50 concentration of cAuNPs for 48 h. For scanning electron microscopy (SEM), cells were grown on thermanox cover slips and after the incubation period fixed permanently using 2% glutaraldehyde. Post fixation was performed using 1% osmium tetroxide. After washing with 0.1 M sodium cacodylate they were dehydrated in a series of acetone-water and acetone-HMS mixture. The samples were dried using a lyophilizer and stored in a dry place. Before viewing, the samples were sputter coated. Then the cells were observed under FEI Quanta FEG 200 at 30 kV and digital images acquired.
For TEM analysis, the cells after treatment as above, were trypsinised and primarily fixed in 2.5% glutaraldehyde prepared in 0.1 M sodium cacodylate buffer for 4 h and post fixed in 1% OsO4 for 2 h. Each fixation step is followed by washing the cells with 0.1 M sodium cacodylate buffer for 10 min. They were then dehydrated through a graded series of acetone-water mixture (30, 50, 70, 80 and 90%) for 20 min each and in 100% acetone twice for 20 min. The cells were treated each time with propylene oxide for 10 min after treating with 100% acetone. The cells were then in-filtered with resin by passing them through a graded series of acetone-resin mixture (25, 50 and 75%) for 2 h and in 100% overnight. The resin mixture consisted of Embed 812 resin, dodecenyl succinic anhydride (DDSA), Nadic methylanhydride (NMA) and 2,4,6-Tris(dimethylaminomethy)-phenol (DMP-30). The samples were embedded in resin �easymoulds� and allowed to polymerize at 60 �C for 48 h. The samples were cut into ultra thin sections, placed on copper grids and stained using uranyl acetate and lead citrate. The samples were then observed in JEOL JEM 1400 operated at a voltage of 80 kV and images acquired.
Flow cytometric studies
Flow cytometry was utilized to find out whether apoptosis is the mode of cell death. 2 X 105 cells were seeded in 12 well plates and treated with 23, 45 and 90 �g/ml of cAuNPs.  After 48 h, the cells were washed with PBS and incubated with 2 �L each of annexin V-FITC and PI stain for 20 min in the dark. The fluorescence of FITC (FL-1 channel (530 nm)) and PI (FL-2 channel (585 nm)) of the stained cells was measured using flow cytometer (FACS Calibur, Beckton Dickinson, Inc., USA).
For cell cycle analysis the cells treated as above were washed with PBS, trypsinised, pelleted, fixed in 70% ice cold ethanol and left overnight. After washing off the ethanol with PBS, 50 �g each of PI and RNase were added and incubated for 30 min in the dark. The cells were then analysed by flow cytometry in FL-2 channel (585 nm) for PI fluorescence. About 20,000 events were recorded for each sample. The data acquired was analysed using CellQuest Pro software. 
Assessment of DNA damage
The cells (1 X 106) were treated with IC50 concentration of cAuNPs. After incubation for 48 h the cells were washed with PBS and lysed on ice with lysis buffer containing 50 mM Tris-HCl (pH 7.5), 20 mM EDTA and 1% NP-40. The supernatants forming the lysates were collected by centrifugation. These were then incubated at 56 �C with RNase (5 mg/mL) and SDS (1%) and then in proteinase K (2.5 mg/mL) for 2 h each. DNA was precipitated from the lysate with 0.5 volume of 10 M ammonium acetate and 2.5 volumes of 70% ice-cold ethanol at -80 �C overnight. The isolated DNA was suspended in Tris (10 mM)-EDTA (25 mM) buffer at pH 8.0. 1.5% agarose gel electrophoresis was performed in Tris (89 mM), borate (89 mM) and EDTA (2 mM) buffer (pH 8.0) containing EtBr (0.5 �g/mL) for 4 h at 60 V. The gel was imaged using gel documentation system (BIORAD).    
Signaling molecules involved in apoptosis
Production of reactive oxygen species (ROS) by cAuNPs was analysed using DCFH-DA. About 20 X 103 cells were treated with 23, 45 and 90 �g/ml of the cAuNPs for 24, 48 and 72 h. After the treatment period, they were washed with PBS and incubated with DCFH-DA (10 �M), suspended in 200 �L of PBS supplemented with 20 mM glucose at 37 �C for 30 min in the dark. ROS production was detected by measuring the fluorescence signals (Ex: 488 nm, Em: 530 nm). For measurement of mitochondrial membrane potential (MMP), cells treated as above were exposed to JC-1 dye. Their fluorescence signals were measured (Red � Ex: 550 nm, Em: 600 nm and Green � Ex: 485, Em: 535 nm). 
Western blot analysis was performed to find out the proteins involved in apoptosis. 1X 106 cells were treated with IC50 values of cAuNPs for 48 h. Proteins were isolated using the cell lysis buffer (RIPA) composed of 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 10 mM Tris-HCl (pH 8.0), 1 mM sodium orthovanadate, 2 �g/mL aprotinin, 10 �g/mL leupeptin, 1 mM PMSF and 1 �g/mL pepstatin. The buffer was added to cells and kept for 30 min on ice.  The proteins were then quantified and run on an SDS-PAGE apparatus. After protein separation the gel was transferred to PVDF membrane. 5% skimmed milk powder was used to block the membrane, and then washed with TBS-tween 20 (TBST). The membrane was incubated overnight at 4 �C with mouse monoclonal antibody specific to the proteins Bax, Bcl-2, PARP and �-actin. The blots were then washed in TBST and incubated in anti-mouse secondary antibody in TBS for 2 h. After further washing in TBS solution they were developed using ECL Western Blotting substrate. The blots were imaged in Thermo Scientific myECL Imaging system.
Statistical analysis
Stern - Volmer plots were constructed using origin 6.1. All the cytotoxic studies have been statistically analysed using Graph Pad Prism 5 software. p values d" 0.05 is considered to be statistically significant.
Results
The anti-cancer activity of the stable and uniform cAuNPs synthesized previously in our laboratory, [19] has been probed in breast cancer cells MCF-7. It is well-known that once inside a biological media the surface chemistry of the AuNPs are modified by the formation of a protein corona. This in turn governs the response of cells such as internalization, toxicity etc. Hence we first investigated the interactions between cAuNPs and proteins of the biological media with BSA as a standard protein.
Formation of a protein corona
The interaction of cAuNPs with BSA and culture media has been studied by fluorescence spectroscopy (Fig. 1). The cAuNPs show a concentration dependent decrease in fluorescence measurements of BSA indicating their ability to quench the fluorescence (Fig. 1a). This results in an increase in FL/FR ratio. The corresponding Stern-Volmer plot gives the value of the constant to be 1*104 L mol-1 (Fig. 1b). The quenching rate constant kq has been calculated to be 2*1013 M-1 s-1 indicating a static quenching mechanism. The number of binding sites (n) is calculated to be 0.9. This is almost equal to 1 indicating that the average number of BSA binding to each cAuNP is 1. A similar decrease in fluorescence quenching has been observed when the cAuNPs are suspended in cell culture medium (Fig. 1c). From TEM observations a layer of proteins is visualized around the cAuNPs when incubated in cell culture medium confirming the formation of protein corona (Fig 1d). The size of the corona is found to be around 5 nm.
Effect on viability and proliferation
On exposure of MCF-7 cells to different concentrations of cAuNPs a concentration and time dependent decrease in viability has been observed (Fig. 2a). Treatment with 23 and 45 �g/ml of cAuNPs for 48 h decreases the viability to 63 and 48% respectively.  The viability value decreases to as low as 25% on treatment with 90 �g/ml for 72 h. On the other hand normal breast cells HBL-100 exposed to cAuNPs show a much lower toxic effect (Fig. 2b). Cells are found to be 90% viable on treatment with all the three concentrations up to 48 h. Treatment with 23 and 45 �g/ml shows a viability of 95 and 90% respectively at 72 h which decreases to 73% only on treatment with 90 �g/ml. These results clearly point out to the cell specific response of cAuNPs, with them being biocompatible towards normal breast cells and toxic to cancerous cells. The IC50 value of cAuNPs for MCF-7 cells has been calculated to be 35 �g/ml for 48 h. The effect of curcumin alone on MCF-7 cells has been investigated by treating the cells with curcumin at concentrations corresponding to those in cAuNPs (Fig. 2c). While no significant decrease in viability is observed on treatment with 1.75 �g/ml curcumin it decreases to 73% at 7 �g/ml concentration. This difference in viability by cAuNPs and curcumin alone points out to a synergistic effect of curcumin with AuNPs. 
The ability of cAuNPs to inhibit the proliferation of MCF-7 cells has also been assessed (Fig. 2d). The proliferation value decreases to 80 and 76% on treatment with 23 �g/ml for 48 and 72 h respectively. The corresponding values for 90 �g/ml are 37 and 39%. These results show that maximum change in proliferation occurs at 48 h of treatment. 
Morphological changes 
On treatment with cAuNPs the MCF-7 cells show morphological changes characteristic to apoptosis (Fig. 3). Direct visualization using phase contrast microscopy revealed apoptotic blebs on cells treated with 23 �g/ml of cAuNPs for 24 h (Fig. 3a). At higher concentrations patches of cells with membrane dissolution could be observed which then gets rounded off and detaches from the substratum. Fluorescence microscopic observation of treated cells after dual staining with EtBr/AO also confirms cell death (Fig. 3b). While control cells fluoresce green, a concentration dependent decrease in green fluorescence and increase in red fluorescence is seen in treated cells. Apoptotic blebs are visible at 24 h and spherical morphology of cells with yellowish orange appearance features at 48 h. 
Ultra-structural studies 
Visualization through SEM shows the appearance of multiple blebs characteristic of apoptosis (Fig. 4a). TEM observations show control cells with numerous filopodia while their absence is evident on treated cells. This detaches the cells from their substratum which then gets rounded off. Swollen mitochondria characteristic to its leakiness during apoptosis is also prominent (Fig. 4b). The toxicity caused by cAuNPs to MCF-7 cells could be further explained on the basis of whether they are internalized. TEM experiments clearly illustrate the internalization of cAuNPs by MCF-7 cells (Fig. 4c). They are found to be present near the cell membrane with individual particles scattered throughout the cytoplasm. After finding out that the internalization of cAuNPs covered by the protein corona results in toxicity to cells, further studies were conducted to elucidate the mode of cell death.
Apoptotic mode of cell death
As cells show apoptotic features during morphological observations this has been further evaluated through flow cytometry. Dual staining of cells with annexin-V FITC/PI sorted cells into different populations representing viable, early and late-apoptotic and necrotic cells (Fig. 5a). A gradual decrease in the percentage of unstained population representing healthy, viable cells has been observed as the concentration of cAuNPs increases. The population of viable cells decreases from 80% in control to 75 and 43% on treatment with 45 and 90 �g/ml of cAuNPs. PI positive cells increases from 7% in control to 35% on treatment with 90 �g/ml.
Cell cycle analysis determines the percentage of cells in different phases depending upon their DNA content. Cells in their hypodiploid state accumulate in the sub-G1 fraction and are considered apoptotic. The cell population in sub-G1 fraction increases from 6% in control to 20, 40 and 65% on treatment with 23, 45 and 90 �g/ml of cAuNPs respectively (Fig. 5b). 
Condensation of chromatin is a characteristic feature during apoptosis. DAPI staining of cAuNPs treated MCF-7 cells reveals prominent bluish appearance of condensed crescent shaped chromatin. On the other hand control cells due to less chromatin condensation and a healthy nucleus show lesser staining (Fig.  5c).
DNA fragmentation
Apoptosis results in the fragmentation of DNA to smaller nucleotide units resulting in a ladder like pattern. Agarose gel analysis of DNA of MCF-7 cells treated with cAuNPs show a similar pattern confirming that apoptosis is the mode of cell death (Fig. 6a). 
Involvement of ROS, MMP and apoptotic proteins in cell death
The signaling molecules that bring about apoptosis in cAuNPs treated MCF-7 cells have been investigated. Because oxidative stress is a key factor for DNA fragmentation, generation of ROS was investigated through DCFH-DA fluorescence. The results indicate an increase in fluorescence measurement in a range between 3-3.5 on treatment with all the three concentrations of cAuNPs after 48 h (Fig. 6b). Maintenance of MMP is important for homeostasis and its depolarization marks apoptosis which has been analyzed using JC-1 dye. A decrease in red to green ratio from 1 in control to 0.77, 0.55 and 0.39 on treatment with 23, 45 and 90 �g/ml of cAuNPs for 48 h indicates depolarization of mitochondria (Fig. 6c). 
The proteins involved in apoptosis have also been studied for their expression by Western blotting (Fig. 6d). The pro-apoptotic protein Bax is found to be over expressed while the anti-apoptotic protein Bcl-2 remains stable. A fold increase in the ratio of Bax/Bcl-2 from 1 in control to 3.2 on treatment confirms that apoptosis is mediated by the up regulation of Bax. Similarly cleavage of the 115 kDa PARP protein to 85 kDa fragment has also been observed confirming apoptotic mode of cell death.
Discussion
The study demonstrates the anti-carcinogenic effects of cAuNPs towards MCF-7 cells and also provides insight into the underlying mechanism. Inside the biological medium cAuNPs form a protein corona, and are then found to get internalized resulting in generation of ROS, decreasing MMP and activation of proteins bringing about an apoptotic mode of cell death.
Understanding the formation of corona around the NPs in a biological medium is inevitable to elucidate the response of cells to NPs. Decrease in the fluorescence intensity of BSA with increasing concentrations of cAuNPs clearly indicates their interaction with the cAuNPs. Energy transfer to metal particles has been reported earlier and AuNPs are found to exhibit such behaviours [20]. The increase in FL/FR ratio of emission maximum as concentration increases points out to a blue shift indicating hydrophobic nature of interaction. This has been reported to be due to intrinsic change in the conformation of albumin placing the tryptophan residues in a more hydrophobic environment due to the protein interaction with AuNPs [21]. The formation of a thin layer of protein complex around the cAuNPs illustrate protein corona over cAuNPs. Similar observation by Walczyk et al. (2010) [22] supports our evidence.
Data obtained from viability studies show the biocompatible nature of cAuNPs towards non-tumorigenic cells. When compared to MCF-7 cells, very small decrease in viability (around 10% on treatment with 90 �g/mL) has been observed in HBL-100 cells clearly pointing out their cell specific response. This is important in the context that AuNPs synthesized using plant extracts such as, S. portulacastrum  at a concentration of 70 �g/mL produces 50% toxicity in HBL-100 cells [23]. That capping agents play important role in toxicity has been reported earlier [24]. It is also evidenced in our previous study, where cAuNPs are found to be non-toxic to red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) [19], when compared to citrate reduced AuNPs [25]. The ability of curcumin to protect normal cells is further supported by studies where curcumin treatment resulted in cell death in MCF-7 but not in normal MCF-10A breast cells [26]. 
The higher potential of cAuNPs in inducing anti-carcinogenic effect is demonstrated by its ability to decrease the viability of MCF-7 cells to about 25% on treatment with 90 �g/mL. The concentration of curcumin present in 90 �g/ml of cAuNPs is found to be about 7 �g/ml. But 20 �M (7.3 �g/ml) of free curcumin produces no cytotoxicity in MCF-7 cells [27]. These values suggest to a synergistic effect produced when curcumin is in conjugation with AuNPs. That anti-cancer drug loaded into metal nanoparticle produces synergistic effect in MCF-7 cells has been reported earlier and supports our evidence [28].
It is also important to note that a very small concentration of curcumin (7 �g/ml) produces a sharp decrease in viability (25%). Other studies using curcumin conjugated AuNPs corroborates with this value [14, 15, 29]. Hyaluronic acid solubilised curcumin reduced AuNPs reduces the viability of HeLa, Glioma and Caco-2 cells by around 20%, where the concentration of curcumin is 6.3 �g/ml [14]. Similar values have been reported with curcumin conjugated PVP capped AuNPs against TZM-b1 cells [15]. Curcumin loaded into PEGylated Xanthan gum stabilized AuNPs is also found to decrease the viability of murine melanoma cells (B16F10) [29]. All these reports emphasizes the increased potential of curcumin conjugated AuNPs to induce anti-carcinogenicity. But the important distinction in our study is that while all the other reports use external agents for curcumin conjugation with AuNPs we could bring about similar levels of cytotoxicity using AuNPs synthesized by curcumin alone. Thus we propose a curcumin NP conjugate which is prepared very well adhering to the principles of green chemistry that show good anti-cancer efficacy. 
Characteristic features such as formation of blebs, rounding off of the cells and detachment from the substratum as visualized through phase contrast microscope and the decrease in the green fluorescence intensity on EtBr/AO staining indicates apoptotic mode of cell death. AuNPs reduced by polyamine derivatives shows similar rounding off and formation of clusters in MCF-7 cells which is attributed to apoptosis [30]. AuNPs conjugated to quercetin also show such a decrease in green fluorescence intensity and condensed chromatin in MCF-7 cells which characterize apoptotic mode of cell death [31]. Ultra structural features such as disappearance of microvillus, formation of multiple blebs and detachment of cells confirm apoptotic mode of cell death [32]. Because cAuNPs are found to get internalized, induction of apoptosis can be attributed to cellular changes triggered due to its uptake [14, 16].
Flow cytometric results reveal the presence of cells in late apoptotic fraction. Cells are found to get arrested in sub-G1 phase indicating accumulation of fragmented DNA at higher concentrations. Similar result has been observed in MCF-7 on exposure to AuNPs synthesized using kaempferol [32] which further strengthens our inference. Changes in nuclear morphology such as condensed chromatin visualized through DAPI staining also indicates apoptotic mode of cell death. MCF-7 cells treated by quercetin conjugated AuNPs are also reported to show similar changes [31].
The biological effects of NPs are controlled by their surface chemistry which affects its interactions with the medium and consequently cells. Cell membrane is an important barrier for internalization [33, 34]. The presence of cAuNPs scattered throughout the cytoplasm suggests endocytosis where the corona consisting of proteins of the biological fluid might help in their uptake as evidenced earlier [35]. The function of such a corona is important in that it protects the cell from early cell response such as clearance, inflammation etc. This retains their original properties such as charge, generation of free radicals etc. resulting in cell death. Once inside the lysosomes the corona gets degraded exposing the NPs [36]. By a similar mechanism, the presence of protein corona might aid in internalization of cAuNPs which then gets degraded in the lysosomes exposing bare cAuNPs in the cell. Localization of morin reduced AuNPs into lysosomes has been previously reported form our laboratory [37].
cAuNPs increases ROS generation resulting in depolarization of the mitochondria, key features of apoptosis. The high surface to volume ratio of AuNPs and the specific configuration of surface Au atoms are reported to produce ROS from dioxygen [38, 39]. In addition chemotherapeutic drug such as curcumin exerts their effects by generating ROS [40]. This might explain the synergistic effect of cAuNPs where the gross decrease in viability of MCF-7 might be due to the increased ROS levels produced by either the charged reductant or the catalytic activity of bare Au core. Curcumin loaded nanoceria particles also show ROS generation which degrades the proteins and lipids of the membrane resulting in leakage of mitochondria and decreased MMP [41]. Apoptosis triggered by different NPs are reported to occur by endosomal uptake followed by localization in lysosomes which can result in mitochondrial activation [42]. Reports on lung cancer cells (A549) exposed to S. portulacastrum reduced AuNPs suggests apoptosis induction to be due to increased production of ROS sensitizing mitochondrial membrane to release apoptotic protein [23]. 
Alterations in the balance of expression levels of pro- and anti-apoptotic proteins regulate apoptosis. Pro-apoptotic proteins such as Bax activate mitochondrial mediated apoptosis. The increased Bax levels and consequently Bax/Bcl-2 ratios on cAuNPs treatment confirms involvement of mitochondria in apoptosis resulting in inhibition of cell proliferation.  Another important characteristic of apoptosis is cleavage of PARP, also observed on treatment with the cAuNPs. Breast cancer cells MDA-MB-231, treated with the curcumin, increased levels of Bax resulting in apoptosis [43]. Increase in Bax levels has been observed in MCF-7 cells on treating with 23 �g/mL of chitosan reduced AuNPs [44]. These reports strengthen our observations that both AuNPs and curcumin has the ability to induce apoptosis by increasing Bax levels. DNA fragmentation, hall mark feature of apoptosis is observed on cAuNPs treatment further confirming apoptotic mode of cell death. The ability of Acalypha indica reduced AuNPs to produce DNA laddering of breast cancer cell has been observed earlier [45].
These results clearly suggest the ability of cAuNPs in inducing apoptosis through ROS mediated mitochondria dependent pathway. The mechanism of action of cAuNPs in inducing apoptosis in MCF-7 cells can be substantiated under the steps as illustrated in the Scheme 1. (1) The cAuNPs interacts with the proteins in the cell culture medium to form a corona. (2) Internalization occurs through endocytosis. (3) The cAuNPs gets sequestered inside lysososmes. (4) Once in the lysosomes the outer corona might get digested by the lysosomal enzymes and the cAuNPs with bare curucmin as the capping agent are exposed. (5) The cAuNPs might then act synergistically to generate ROS. (6) Increased ROS levels decrease MMP resulting in leakiness of mitochondria and increases expression of Bax. (7) This leads to final stages in cell death like cleavage of PARP, fragmentation of DNA and chromatin condensation culminating in apoptosis.
Conclusion
The study proves the ability of cAuNPs to induce apoptosis mediated by ROS generation in MCF-7 cells. It emphasizes on the diverse potential of curcumin as it retains its biological activity even when acting as a reducing and capping agent for AuNPs. After internalization, the cAuNPs constituting the charged reductant curcumin and Au core exerts a synergistic effect on MCF-7 cells causing toxicity. At the same time they show non-toxic effects in normal breast cells. These results provide a basic understanding for the molecular basis of apoptotic induction by cAuNPs. They also highlight the promising potential of cAuNPs to be used as a drug against breast cancer.
Acknowledgements
The authors thank the Director, Central Leather Research Institute (CLRI), Chennai, India for the support provided. They also gratefully acknowledge Council of Scientific and Industrial Research (CSIR), India for financial support provided through the network project STRAIT (CSC0102). One of the authors (K.S) acknowledges CSIR, India for the Senior Research Fellowship. 
Conflict of Interest
All the authors declare that they have no conflict of interest.
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Fig. 1 Formation of protein corona (a) Fluorescence quenching of BSA by different concentrations of cAuNPs (inset shows FL/FR ratio of the spectra) (b) corresponding Stern-Volmer plot (c) fluorescence quenching of proteins in DMEM with FBS medium by cAuNPs and (d) TEM images of cAuNPs with corona               
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h��5�CJOJQJaJlls. (c) Effect of curcumin alone on viability of MCF-7 cells. (d) Effect of cAuNPs on cell proliferation. Values represent mean � S.D of three independent experiments. * P < 0.05, ** P < 0.01 and *** P < 0.001
Fig. 3 Morphological changes on treatment of MCF-7 cells with cAuNPs. (a) Phase contrast microscopic images. (b) Fluorescence images of the cells dual stained with EtBr/AO.  Scale bar represents 20 �m
Fig. 4 Ultrastructural studies on MCF-7 cells treated with IC50 concentration of cAuNPs. (a) SEM images showing rounded cells with multiple blebbing, (b) TEM images showing swollen mitochondria and (c) internalized cAuNPs          
Fig. 5 Flow cytometric analysis of MCF-7 cells treated with cAuNPs for 48 h. (a) Representative dot plots of cells stained with annexin-V FITC/PI, (b) cell cycle analysis by PI staining method. Values represent mean � S.D of three independent experiments. (c) DAPI staining of control and treated MCF-7 cells
Fig. 6 Signaling molecules involved in inducing apoptosis. (a) DNA fragmentation pattern on treatment with IC50 values of cAuNPs for 48 h, (b) measurement of ROS production (c) measurement of changes in MMP and (d) Western blot analysis of apoptotic proteins. For ROS and MMP measurements each value represent mean � S.D of three independent experiments. * P < 0.05, ** P < 0.01 and *** P < 0.001
Scheme 1 Schematic diagram depicting the mechanism of induction of apoptosis by cAuNPs in MCF-7 cells. The steps involved are (1) formation of protein corona around cAuNPs (2) endocytosis (3) sequestration in lysosomes (4) degradation of corona and exposure of bare cAuNPs (5) generation of ROS (6) depolarization of mitochondria and increased Bax expression (7) final changes that execute the process of apoptosis
 


















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