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Oxycodone enhances antitumor effect of paclitaxel on human breast cancer SKBR3 cells in vitro
Fangfang Liu, Hongmei Yuan, Chenyang Xu, Mingjie Mao, Shanwu Feng
Corresponding author
shanwufeng666@163.com

Corresponding author.
Department of Anesthesiology, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, Nanjing, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0008">Introduction</span><p id="para0008" class="elsevierStylePara elsevierViewall">As the most common cancer in females&#44; breast cancer is considered the leading cause of cancer-related death in women&#46;<a class="elsevierStyleCrossRef" href="#bib0001"><span class="elsevierStyleSup">1</span></a> Up to now&#44; surgery is still the most commonly used therapy for breast cancer&#44; and chemotherapy&#44; radiotherapy&#44; endocrinology&#44; immunity and targeted therapy may serve as adjunctive therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0002"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> In decades&#44; great progress has been made in the therapy of breast cancer&#44; however&#44; the perioperative analgesia&#44; treatment of advanced cancer pain and prevention of tumor recurrence have been clinical challenges in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a> Therefore&#44; comprehensive consideration of treatment plans is critical in the management of breast cancer&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">Oxycodone &#40;OXY&#41; is a semisynthetic opioid that can bind to both &#956;-and &#954;-opioid receptors derived from the Bain&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> Increasingly&#44; studies have used OXY in the treatment of moderate to severe perioperative pain and chronic cancer pain&#46; Studies have indicated that OXY can promote or prevent tumor growth and metastasis&#46;<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0007"><span class="elsevierStyleSup">7</span></a> Paclitaxel &#40;PTX&#41; is an effective drug for the chemotherapy of cancers and has been widely applied in clinical&#46; However&#44; the severe side effects and multiple drug resistance greatly limit the wide clinical application of PTX&#46; Hence&#44; the present study aimed to investigate the antitumor effects of PTX combined with OXY on human breast cancer SKBR3 cells <span class="elsevierStyleItalic">in vitro</span>&#44; and explore the potential mechanism&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0009">Materials and methods</span><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0010">Drugs</span><p id="para0010" class="elsevierStylePara elsevierViewall">OXY was obtained from Mundipharma Pharmaceutical Co&#46; Ltd&#46; &#40;Cambridge&#44; UK&#41; and PTX from Yangtze River pharmaceutical group Co&#46;&#44; Ltd&#46; &#40;Jiangsu&#44; China&#41;&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0011">Cell culture and treatment</span><p id="para0011" class="elsevierStylePara elsevierViewall">Human breast cancer SKBR3 cells were provided by the Department of Oncology&#44; Jinling Hospital&#44; General Hospital of Eastern Theater Command &#40;Nanjing&#44; China&#41;&#46; These cells were maintained in Dulbecco&#39;s modified Eagle&#39;s medium &#40;DMEM&#44; KeyGEN BioTECH&#44; China&#41; with the addition of 10 &#37; fetal bovine serum &#40;FBS&#44; Gibco&#44; USA&#41; at 37&#176;C and 5 &#37; CO<span class="elsevierStyleInf">2</span>&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0012">CCK-8 proliferation assay</span><p id="para0012" class="elsevierStylePara elsevierViewall">The cell viability was examined by Cell Counting Kit-8 &#40;CCK-8&#44; APExBIO&#44; USA&#41; according to the manufacturer&#39;s protocols&#46; Briefly&#44; cells were seeded into 96-well plates at a density of 3 &#215; 10<span class="elsevierStyleSup">3</span> cells per well and then incubated at 37&#176;C overnight&#46; Then&#44; these cells were treated with OXY &#40;0&#46;025&#44; 0&#46;05&#44; 0&#46;1&#44; 0&#46;25&#44; 0&#46;5&#44; 1 and 2 mM&#41; and&#47;or PTX &#40;2&#44; 4&#44; 8&#44; 16&#44; 32 and 64 &#956;M&#41; for 24h or 48h&#46; There were at least 5 wells in each group&#44; and the measurement was repeated at least 3 times&#46; In brief&#44; 10 &#956;L CCK-8 solution was dropped to each well&#44; followed by incubation for 1h at 37&#176;C&#46; The cell viability was evaluated by examining the absorbance at 450 nm&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0013">Colony formation assay</span><p id="para0013" class="elsevierStylePara elsevierViewall">Cells were seeded into 6-well plates with a density of 800 cells per well&#44; and subsequently incubated with OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; and&#47;or PTX &#40;8 &#956;M&#41; for 8&#8210;10 days&#46; Then&#44; cell colonies were fixed by the 4 &#37; paraformaldehyde for 15 min and subsequently stained with 0&#46;1 &#37; crystal violet &#40;Beyotime&#44; Jiangsu&#44; China&#41; for 30 min&#46; These cells were photographed using a microscope &#40;Olympus&#44; Tokyo&#44; Japan&#41;&#46; Colonies containing at least 50 cells were scored&#46;</p></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0014">Wound scratch assay</span><p id="para0014" class="elsevierStylePara elsevierViewall">Three lines were delineated at the back of a 6-well plate through a marker&#46; These transverse lines were uniformly drawn at a distance of 0&#46;5&#8210;1 cm between lines with the assistance of a ruler&#44; and the lines passed through the wells&#46; Cells were incubated in 6 well plates&#46; When the cell&#39;s monolayer reached 90 &#37; confluence&#44; each microplate was scratched in three straight lines with a pipette tip&#46; After washing with Phosphate-Buffered Saline &#40;PBS&#41;&#44; the medium was changed to the medium containing 1 &#37; FBS and OXY and&#47;or PTX at different concentrations&#46; Images were captured using a DSC-HX1 digital camera &#40;Sony Corporation&#44; Tokyo&#44; Japan&#41; at each time point &#40;0h&#44; 24h and 48h&#41;&#46;</p><p id="para0015" class="elsevierStylePara elsevierViewall">The migration rate was measured by capturing images at different time points using a digital camera&#46; The width of the wound was measured at the widest point&#44; and the migration rate was calculated as the percentage of the initial wound width that had healed at each time point&#46; At least three independent experiments were performed for each group&#46;</p></span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0015">Transwell migration and invasion assays</span><p id="para0016" class="elsevierStylePara elsevierViewall">Transwell assays were conducted using 24-well plates with the insertion of 8 &#956;m pore-size Transwell &#40;Corning Incorporated&#44; Corning&#44; USA&#41;&#46; Cells treated with OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; and&#47;or PTX &#40;8 &#956;M&#41; were counted and subsequently resuspended in serum-free Dulbecco&#39;s Modified Eagle Medium &#40;DMEM&#41;&#46; 100 &#956;L DEME medium containing 5&#215;105 cells in each group were added to each upper chamber for migrating ability assessment&#46; The lower chambers were added with 800 &#956;L medium containing 20 &#37; FBS&#46; The cells migrated to the lower chamber and were fixed for 5 min by 4 &#37; paraformaldehyde following incubation for 24h&#44; then treated with methanol for 10 min and then 0&#46;1 &#37; crystal violet for 15 min&#46; The cells were counted at a magnification of &#215;100 under a light microscope &#40;Sony Corporation&#44; Tokyo&#44; Japan&#41;&#46; The cell number was evaluated by Image J software and expressed as the average cell number in each field &#40;Rawak Software&#44; Inc&#46; Germany&#41;&#46;</p><p id="para0017" class="elsevierStylePara elsevierViewall">For invasion assays&#44; 50 &#956;L matrix glue with Matrigel &#40;BD Biosciences&#44; USA&#59; 1&#58;8&#41; was added into the upper chambers before adding cells into the upper chambers&#46; Then&#44; the plates were incubated at 37&#176;C for 5h and the following procedures were the same to those above mentioned&#46;</p></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0016">Detection of cell apoptosis by flow cytometry</span><p id="para0018" class="elsevierStylePara elsevierViewall">SKBR3 cells &#40;5&#215;105 cells&#47;well&#41; were seeded into 6 well plates and then incubated at 37&#176;C overnight&#46; Cells were pre-treated with OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; and&#47;or PTX &#40;10 &#956;M&#41; for 24h&#46; According to the manufacturer&#39;s protocols&#44; cells were collected and resuspended in 195 &#956;L binding buffer&#46; Subsequently&#44; 5 &#956;L Annexin V-FITC &#40;Beyotime&#44; Jiangsu&#44; China&#41; and 5 &#956;L propidium iodide &#40;PI&#44; Beyotime&#44; Jiangsu&#44; China&#41; were added to each cell suspension&#44; followed by 20 min incubation at room temperature in dark&#46; Cell apoptosis was evaluated by flow cytometry &#40;BD Biosciences&#44; USA&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0017">Western blotting</span><p id="para0019" class="elsevierStylePara elsevierViewall">After different treatments&#44; cells were incubated with RIPA buffer at 4&#176;C for 10 min&#46; Total protein was collected through the 12&#44;000&#215; g centrifugation for 30 min &#40;4&#176;C&#41; and quantified with a BCA kit &#40;NCM Biotech&#44; Suzhou&#44; China&#41;&#46; Proteins were separated by 10 &#37; SDS-PAGE and transferred onto PVDF membranes &#40;EMD Millipore&#44; Billerica&#44; MA&#41;&#46; After 1h block with 5 &#37; fat-free milk&#44; the membranes were incubated with primary antibodies overnight at 4&#176;C&#46; Then the secondary antibodies were applied in the incubation with the membranes for 1h at room temperature after washing with TBST&#46; The protein bands were visualized with ECL reagent &#40;Beyotime&#44; Jiangsu&#44; China&#41; and then quantified&#46;</p><p id="para0020" class="elsevierStylePara elsevierViewall">The primary antibodies used in present study were as follows&#58; anti-Bcl2 &#40;1&#58;1000&#44; ab196495&#41;&#44; anti-Bax &#40;1&#58;2000&#44; ab3191&#41;&#44; anti-E-cadherin &#40;1&#58;2000&#44; ab238099&#41;&#44; anti-N-cadherin &#40;1&#58;2000&#44; ab254512&#41;&#44; anti- GAPDH &#40;1&#58;5000&#44; ab181602&#41;&#44; anti-PI3K &#40;1&#58;5000&#44; ab32089&#41;&#44; anti-AKT &#40;1&#58;5000&#44; ab81283&#41;&#44; anti-mTOR &#40;1&#58;5000&#44; ab32028&#41;&#44; anti-LC3-&#8545;&#40;1&#58;5000&#44; ab222776&#41;&#44; anti-Beclin1&#40;1&#58;5000&#44; ab207612&#41;&#44; anti-p-AKT &#40;1&#58;5000&#44; ab8805&#41; and anti-p-mTOR &#40;1&#58;5000&#44; ab84400&#41; &#40;Abcam&#44; UK&#41;&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0018">Transmission electron microscopy</span><p id="para0021" class="elsevierStylePara elsevierViewall">Cells were collected by centrifugation at 1000 R &#47;min for 5 min&#44; and subsequently incubated with 2&#46;5 &#37; glutaraldehyde at 4&#176;C for 24h&#46; Then&#44; the cells were post-fixed in 1 &#37; osmium tetroxide solution for 1h&#44; dehydrated in 90 &#37; acetone for 15 min and in 100 &#37; acetone for 10 min &#40;3 times&#41;&#44; and finally embedded in Epon LX-112 resin&#46; The blocks were sliced into ultrathin slices and double-stained with uranyl acetate and lead citrate&#46; Autophagic bodies were observed under a transmission electron microscope &#40;IEM-1200exv&#41;&#46;</p></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0019">Statistical analysis</span><p id="para0022" class="elsevierStylePara elsevierViewall">There were at least three independent experiments in each group and all the data are expressed as mean &#177; standard deviation&#46; Student&#39;s <span class="elsevierStyleItalic">t</span>-test was conducted to measure the comparison between two groups&#44; and a one-way analysis of variance followed by Dunnett&#39;s test was applied in multiple groups&#46; A value of p &#60; 0&#46;05 was considered statistically significant&#46;</p></span></span><span id="sec0013" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0020">Results</span><span id="sec0014" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0021">OXY enhances the effect of PTX on the proliferation of SKBR3 cells</span><p id="para0023" class="elsevierStylePara elsevierViewall">To investigate the effects of OXY and&#47;or PTX on the malignant biological behaviors of SKBR3 cells&#44; the viability and colony-forming ability of SKBR3 cells were evaluated by CCK-8 and colony formation assays&#46; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; inhibited the proliferation of SKBR3 cells in a dose-dependent manner within 48h &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1A</a>&#41;&#46; Meanwhile&#44; 8 &#956;M PTX restrained the proliferation of SKBR3 cells significantly and dementated about 50 &#37; growth inhibition &#40;p &#60; 0&#46;05&#41;&#46; However&#44; increasing the concentration of PTX had no significant effect on the inhibition rate at 24h &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1B</a>&#41;&#46; Therefore&#44; 8 &#956;M PTX was used in the following experiments&#46; Moreover&#44; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; markedly augmented the outstanding antiproliferative effect of PTX on the SKBR3 cells&#44; which was dose-dependent &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1C</a>&#41;&#46; Similarly&#44; colony formation assay revealed that OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; remarkably decreased the clonogenic survival of SKBR3 cells within 48 h&#44; and OXY &#40;1 mM&#41; significantly reduced the number of clones as compared to OXY &#40;0&#46;25 and 0&#46;5 mM&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1D</a>&#44; p &#60; 0&#46;05&#41;&#46; As shown in <a class="elsevierStyleCrossRef" href="#fig0001">Figure 1D</a>&#44; OXY &#40;0&#46;25 and 0&#46;5 mM&#41; and PTX &#40;8 &#956;M&#41; synergistically decreased the proliferation of SKBR3 cells within 24h &#40;p &#60; 0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0022">OXY enhanced the effect of PTX on the Migration and Invasion of SKBR3 Cells</span><p id="para0024" class="elsevierStylePara elsevierViewall">The effects of OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; and&#47;or PTX &#40;8 &#956;M&#41; on the migration and invasion of SKBR3 cells were further examined by Transwell and wound scratch experiments&#46; OXY treatment significantly diminished the migration and invasion of SKBR3 cells in a dose-dependent manner within 48h &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2A</a>&#44; B&#41;&#46; Additionally&#44; OXY enhanced the inhibitory effect of PTX on the SKBR3 cells within 24h&#44; and OXY at the highest concentration &#40;1 mM&#41; achieved the most obvious effect &#40;p &#60; 0&#46;05&#41;&#46; Wound scratch assay revealed that OXY significantly attenuated the migratory ability of SKBR3 cells in a dose-dependent manner &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2C</a>&#41;&#59; whereas the migratory ability of SKBR3 cells further reduced in a dose&#8209;dependent manner in the OXY plus PTX group &#40;<a class="elsevierStyleCrossRef" href="#fig0002">Fig&#46; 2D</a>&#44; p &#60; 0&#46;05&#41;&#46; In other words&#44; the migration distance in the OXY &#40;1 mM&#41; group was significantly longer as compared to the control&#46; Moreover&#44; the distance in the OXY &#40;1 mM&#41; plus PTX group was markedly longer than in the PTX group &#40;p &#60; 0&#46;05&#41;&#46;</p><elsevierMultimedia ident="fig0002"></elsevierMultimedia></span><span id="sec0016" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0023">OXY enhanced PTX-induced apoptosis of SKBR3 cells</span><p id="para0025" class="elsevierStylePara elsevierViewall">The apoptotic rate significantly increased after OXY treatment &#40;p &#60; 0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3A</a>&#41;&#46; Moreover&#44; the antiproliferative effect of PTX was significantly augmented in the presence of OXY&#44; compared with cells treated with PTX alone &#40;p &#60; 0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3A</a>&#41;&#46; Besides&#44; PTX-induced cell apoptosis was enhanced in the presence of OXY &#40;p &#60; 0&#46;05&#59; <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3A</a>&#41;&#46;</p><elsevierMultimedia ident="fig0003"></elsevierMultimedia><p id="para0026" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3B</a>&#44; the Bcl2 expression decreased&#44; while Bax expression increased after OXY treatment &#40;p &#60; 0&#46;05&#41;&#46; This effect of OXY &#40;1 mM&#41; was the most evident in the OXY group&#46; As expected&#44; Bax expression in cells further increased&#44; while Bcl-2expression further decreased after treatment with PTX and OXY as compared to cells treated with PTX &#40;<a class="elsevierStyleCrossRef" href="#fig0003">Fig&#46; 3B</a>&#41;&#46; These findings implied that OXY enhanced PTX-induced apoptosis in SKBR3 cells&#46;</p></span><span id="sec0017" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0024">OXY promoted the PTX-induced inhibition of epithelial mesenchymal transition in SKBR3 cells</span><p id="para0027" class="elsevierStylePara elsevierViewall">Studies have shown that Epithelial Mesenchymal Transition &#40;EMT&#41; is closely related to the tumor metastasis and invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0003"><span class="elsevierStyleSup">3</span></a> Therefore&#44; EMT-related proteins were assessed in the present study&#46; As compared to cells treated with PTX alone and the control group &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0004">Fig&#46; 4</a>&#41;&#44; OXY increased the expression of epithelial marker E-cadherin while decreasing the expression of mesenchymal marker N-cadherin in a dose-dependent manner These results demonstrated that OXY inhibited EMT to compromise the migration and invasion of SKBR3 cells and OXY exerted synergistic effect with PTX&#46;</p><elsevierMultimedia ident="fig0004"></elsevierMultimedia></span><span id="sec0018" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0025">OXY combined with PTX upregulated expression of autophagy-related proteins and decreased PI3K&#47;AKT&#47;mTOR-related molecules in SKBR3 Cells</span><p id="para0028" class="elsevierStylePara elsevierViewall">To explore the mechanisms by which OXY and&#47;or PTX restrained the proliferation and enhanced apoptosis of SKBR3 cells&#44; molecules in the PI3K&#47;AKT&#47;mTOR signalling pathway and autophagy were detected by Western blotting&#46; The protein expression of LC3-&#8545; and Becline-1 &#40;two markers of autophagy&#41; was detected&#46; OXY treatment significantly diminished the levels of p-AKT and p-mTOR &#40;p &#60; 0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5A</a>&#41; in a dose-dependent manner without affecting the expression of PI3K&#44; AKT and mTOR in SKBR3 cells in comparison with cells treated with PTX alone and cells in the control group&#46; In contrast&#44; the expression of LC3-&#8545; and Becline1 markedly increased by OXY and&#47;or PTX &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 5B</a>&#41;&#46; These findings confirmed that OXY inhibited the phosphorylation of PI3K&#47;AKT&#47;mTOR signalling pathway and affected the process of autophagy&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0019" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0026">OXY and combination of OXY with PTX promote SKBR3 cells autophagy</span><p id="para0029" class="elsevierStylePara elsevierViewall">Autophagy plays an important role in the cancer progression&#44; and Transmission Electron Microscope &#40;TEM&#41; is the gold standard for the detection of autophagy currently&#46; The structural morphology and number of autophagosomes and autolysosomes in cells can be observed by TEM&#46; As displayed in <a class="elsevierStyleCrossRef" href="#fig0006">Figure 6</a>&#44; SKBR3 cells in the control group were immature&#44; with fewer cell connections&#44; and no autophagosomes and autolysosomes formed&#46; After treatment with PTX or OXY &#40;1 mM&#41;&#44; the proportion of cell cytoplasm increased&#44; vesicles with double-layer membrane structure appeared in the cytoplasm with a size of about 500 nm&#44; and cells appeared autophagosome-like structures&#46; Moreover&#44; treatment with PTX and OXY &#40;1 mM&#41; further enhanced the autophagy of SKBR3 cells&#46;</p><elsevierMultimedia ident="fig0006"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0027">Discussion</span><p id="para0030" class="elsevierStylePara elsevierViewall">Breast cancer is the mainly malignancy in women worldwide&#44; and its morbidity and mortality are still rising&#46; Surgery is still the therapy of choice for breast cancer in these patients&#46; Recently&#44; whether perioperative pharmacotherapy affects the recurrence and metastasis of cancers and promotes the occurrence and development of tumours has attracted extensive attention&#46;<a class="elsevierStyleCrossRefs" href="#bib0001"><span class="elsevierStyleSup">1-3</span></a></p><p id="para0031" class="elsevierStylePara elsevierViewall">Opioids and anticancer drugs are the most commonly used drugs in the treatment of cancer patients&#46; Generally&#44; both opioids and anticancer drugs are simultaneously administered to patients in clinical practice&#44; especially those with cancer metastasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">5-7</span></a> OXY&#44; a semisynthetic &#956;-and &#954;-opioid dual receptor agonist&#44; has been extensively used for the anesthetic pre-medication and the pain management caused by cancer metastasis&#46; Currently&#44; evidence shows that OXY can affect multiple processes in the cancer progression&#44; including immune function&#44; angiogenesis&#44; apoptosis and invasion&#46;<a class="elsevierStyleCrossRef" href="#bib0004"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">5</span></a> PTX is an effective drug used for the chemotherapy of cancers and has been extensively applied in the clinical therapy of breast cancer&#46; The side effects and drug resistance caused by high-dose and long-term paclitaxel treatment have significantly limited its wide use in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0008"><span class="elsevierStyleSup">8</span></a> In recent years&#44; the combination therapy of drugs has become an effective strategy to reduce the side effects and improve the efficacy in the treatment of cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">10</span></a> Hence&#44; the combination of OXY with PTX may be a potential and appropriate treatment for cancer&#46; To investigate the optimal concentration and the synergistic effects of OXY and PTX&#44; SKBR3 cells were treated with OXY and&#47;or PTX&#44; and their biological behaviours were further investigated&#46; The optimal concentration of OXY was examined by CCK-8 assay &#40;<a class="elsevierStyleCrossRef" href="#fig0001">Fig&#46; 1A</a> and B&#41;&#46; In the present study&#44; the concentration of OXY ranged from 0 to 2 mM and that of PTX ranged from 0 to 64 &#956;M&#46; The results indicated OXY at &#60; 0&#46;25 mM was unable to reduce cell survival&#44; and OXY at 0&#46;25&#8210;2 mM could exert inhibitory effects on the SKBR3 cells after treatment for 24&#8210;48h as compared to control group&#46; CCK-8 assay&#44; and colony formation assay indicated that OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; significantly inhibited the proliferation&#44; migration&#44; and invasion of SKBR3 cells&#46; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; significantly induced the apoptosis of SKBR3 cells on flow cytometry and regulated the expression of Bcl2 and Bax in a concentration-dependent manner&#46; This was consistent with previous findings that OXY could synergistically inhibited the growth of lung and breast cancer<a class="elsevierStyleCrossRef" href="#bib0006"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0011"><span class="elsevierStyleSup">11</span></a> Meanwhile&#44; the present results suggested that the combination treatment significantly improved the antitumor effect of PTX&#46;</p><p id="para0032" class="elsevierStylePara elsevierViewall">Accumulating evidence demonstrates that EMT&#44; PI3K&#47;Akt&#47;mTOR signalling pathway&#44; and autophagy play important roles in the tumor progression&#44; metastasis&#44; and chemoresistance&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0012"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> Among metastasis process&#44; EMT transforms adherent epithelial cells into highly mobile mesenchymal cells&#46; Then&#44; the migrating and invading abilities of cancer cells are continuously enhanced&#46; E-cadherin is considered as the characteristic marker in epithelial cells which locating on the parts of adhesion junction and basolateral plasma membrane&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> N-cadherin is mainly expressed in cells from mesenchymal origin which was closely related to the invasiveness of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> Few studies have reported the effect of opioids on the EMT of SKBR3 cells&#46; The present results showed that OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; elevated the expression of E-cadherin and decreased N-cadherin&#46; This indicates that the effects of OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; on the migration and invasion of breast cancer cells are partly associated with the inhibition of EMT&#46;</p><p id="para0033" class="elsevierStylePara elsevierViewall">PI3K&#47;Akt&#47;mTOR signalling is a key regulator of cellular events such as growth&#44; proliferation&#44; survival and invasiveness in cancers&#44;<a class="elsevierStyleCrossRef" href="#bib0013"><span class="elsevierStyleSup">13</span></a> and has become an attractive target in the therapy of breast cancer&#46; Evidence has showed that morphine can activate the downstream signalling pathway of AKT-mTOR to promote the proliferation&#44; migration&#44; and invasion of cells&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a> However&#44; Helmy et al report that PI3K&#47;AKT pathway was involved in the tramadol induced apoptosis of liver HepG2 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0014"><span class="elsevierStyleSup">14</span></a> In this study&#44; the expression of molecules in the PI3K&#47;Akt&#47;mTOR signalling pathway was further detected in SKBR3 cells treated with OXY or&#47;and PTX&#46; The present results showed that OXY significantly diminished the expression of p-AKT and p-mTOR without affecting the expression of PI3K&#44; AKT and mTOR in SKBR3 cells&#46; These indicate that OXY restraints the malignant behaviours of SKBR3 cells through the phosphorylation of molecules in the PI3K&#47;AKT&#47;mTOR signalling pathway&#44; rather than regulating the expression of these proteins&#46; The present results support OXY as a candidate for the clinical therapy towards breast cancer SKBR3 cells&#46;</p><p id="para0034" class="elsevierStylePara elsevierViewall">Increasing studies have indicated that autophagy functions a crucial role in the pathogenesis of cancers and may be an effective target in the treatment of cancers&#46; LC3&#44; Beclin1 and p62 are autophagy related proteins&#44; which have been considered as independent biomarkers for predicting overall survival and progression-free survival in cancer patients&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a> LC3A is divided into LC3A&#44; LC3B and LC3C&#59; among them&#44; LC3B is most closely related to autophagy&#46; LC3 is involved in all stages of autophagy&#46; When autophagy occurs&#44; LC3-&#8544; is activated and binds to phosphatidylethanolamine&#44; and then it converts into LC3-&#8545;&#46; LC3-&#8545; may promote the formation and maturation of autophagy and aggregate on autophagy bodies&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> Beclin1 is an essential molecule for autophagy&#44; which plays a vital role in the occurrence and development of tumours&#46; Beclin1 expression tends to increase during autophagy&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a> Some studies have indicated that autophagy participated in the proliferation and apoptosis of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0016"><span class="elsevierStyleSup">16</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0017"><span class="elsevierStyleSup">17</span></a> This study confirmed that OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; induced the autophagy of SKBR3 cells by upregulating the levels of autophagy related proteins LC3-&#8545; and Beclin1 and further promoted the autophagy inducing ability of PTX&#46; On TEM&#44; the number and size of autophagic bodies and autophagy vesicles in the OXY &#40;1 mM&#41; group were significantly different from those in the control&#47;PTX group&#46; Above findings indicate that autophagy&#44; EMT and PI3K&#47;Akt&#47;mTOR signalling are involved in the pathogenesis of breast cancer&#46; In recent years&#44; studies have also proposed that there is a complex link among them&#46;<a class="elsevierStyleCrossRef" href="#bib0009"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">15</span></a></p><p id="para0035" class="elsevierStylePara elsevierViewall">There were several limitations in this study&#46; First&#44; the authors did not further explore the pharmacological and toxicological effects of OXY&#46; Second&#44; the authors speculate that oxycodone promotes the antitumor properties of PTX&#44; but the authors did not intervene with the signalling pathway and autophagy to further explore the specific roles of PI3K&#47;Akt&#47;mTOR and autophagy in the effects of OXY and&#47;or PTX on breast cancer cells&#46; This study investigated the fact that autophagy&#44; EMT and PI3K&#47;Akt&#47;mTOR signalling were participate in SKBR3 cells and regulated by OXY alone or combined with PTX&#46; Meanwhile&#44; the authors believed that OXY can promote the apoptosis of SKBR3 cells and enhance the antitumor effects of PTX <span class="elsevierStyleItalic">in vitro</span>&#46;</p></span><span id="sec0021" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0028">Conclusions</span><p id="para0036" class="elsevierStylePara elsevierViewall">The present study indicates that OXY can augment the antitumor effect of PTX on breast cancer <span class="elsevierStyleItalic">in vitro</span>&#46; Therefore&#44; PTX in combination with OXY may serve as a potential strategy for the treatment of breast cancer&#46;</p></span><span id="sec01022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle01029">Availability of data and materials</span><p id="para0038" class="elsevierStylePara elsevierViewall">The data that support the findings of this study are available from the corresponding author upon reasonable request&#46;</p></span><span id="sec0022" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0029">Ethical approval</span><p id="para0039" class="elsevierStylePara elsevierViewall">The manuscript conforms to the STROBE Statement&#46; This experiment does not involve humans and animals&#44; and there is no ethical approval&#46;</p></span><span id="sec0023" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0030">Authors&#8217; contributions</span><p id="para0040" class="elsevierStylePara elsevierViewall">Conceptualization&#58; FL&#59; Data curation&#58; FL&#59; Investigation&#58; FL&#44; HY&#59; Methodology&#58; FL&#44; CX&#59; Validation&#58; MM&#59; Funding acquisition&#58; SF&#59; Writing - original draft&#58; FL&#59; Writing - review &#38; editing&#58; SF&#46;</p></span><span id="sec0024" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0031">Funding</span><p id="para0041" class="elsevierStylePara elsevierViewall">The present study was supported by the National Natural Science Foundation of China &#40;grant nos&#46; 81971045&#41; attributed to the Department of Anesthesiology&#44; Women&#39;s Hospital of Nanjing Medical University&#44; Nanjing Maternity and Child Health Care Hospital&#44; Nanjing&#44; Jiangsu Province&#44; China&#46;</p></span></span>"
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              "titulo" => "Colony formation assay"
            ]
            4 => array:2 [
              "identificador" => "sec0007"
              "titulo" => "Wound scratch assay"
            ]
            5 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "Transwell migration and invasion assays"
            ]
            6 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Detection of cell apoptosis by flow cytometry"
            ]
            7 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Western blotting"
            ]
            8 => array:2 [
              "identificador" => "sec0011"
              "titulo" => "Transmission electron microscopy"
            ]
            9 => array:2 [
              "identificador" => "sec0012"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        5 => array:3 [
          "identificador" => "sec0013"
          "titulo" => "Results"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "sec0014"
              "titulo" => "OXY enhances the effect of PTX on the proliferation of SKBR3 cells"
            ]
            1 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "OXY enhanced the effect of PTX on the Migration and Invasion of SKBR3 Cells"
            ]
            2 => array:2 [
              "identificador" => "sec0016"
              "titulo" => "OXY enhanced PTX-induced apoptosis of SKBR3 cells"
            ]
            3 => array:2 [
              "identificador" => "sec0017"
              "titulo" => "OXY promoted the PTX-induced inhibition of epithelial mesenchymal transition in SKBR3 cells"
            ]
            4 => array:2 [
              "identificador" => "sec0018"
              "titulo" => "OXY combined with PTX upregulated expression of autophagy-related proteins and decreased PI3K&#47;AKT&#47;mTOR-related molecules in SKBR3 Cells"
            ]
            5 => array:2 [
              "identificador" => "sec0019"
              "titulo" => "OXY and combination of OXY with PTX promote SKBR3 cells autophagy"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Discussion"
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        7 => array:2 [
          "identificador" => "sec0021"
          "titulo" => "Conclusions"
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        8 => array:2 [
          "identificador" => "sec01022"
          "titulo" => "Availability of data and materials"
        ]
        9 => array:2 [
          "identificador" => "sec0022"
          "titulo" => "Ethical approval"
        ]
        10 => array:2 [
          "identificador" => "sec0023"
          "titulo" => "Authors&#8217; contributions"
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        11 => array:2 [
          "identificador" => "sec0024"
          "titulo" => "Funding"
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        12 => array:2 [
          "identificador" => "xack786314"
          "titulo" => "Acknowledgments"
        ]
        13 => array:1 [
          "titulo" => "References"
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      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1903409"
          "palabras" => array:4 [
            0 => "SKBR3 breast cancer"
            1 => "Oxycodone"
            2 => "Paclitaxel"
            3 => "Apoptosis"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "highlights" => array:2 [
      "titulo" => "Highlights"
      "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><p id="spara007" class="elsevierStyleSimplePara elsevierViewall"><ul class="elsevierStyleList" id="celist0001"><li class="elsevierStyleListItem" id="celistitem0001"><span class="elsevierStyleLabel">&#8226;</span><p id="para0001" class="elsevierStylePara elsevierViewall">Oxycodone markedly induced the apoptosis of SKBR3 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0002"><span class="elsevierStyleLabel">&#8226;</span><p id="para0002" class="elsevierStylePara elsevierViewall">Oxycodone distinguished enhanced antitumor effect of PTX on SKBR3 cells&#46;</p></li><li class="elsevierStyleListItem" id="celistitem0003"><span class="elsevierStyleLabel">&#8226;</span><p id="para0003" class="elsevierStylePara elsevierViewall">OXY can enhance antitumor effect of PTX on breast cancer <span class="elsevierStyleItalic">in vitro</span>&#46;</p></li></ul></p></span>"
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0003">Background</span><p id="spara008" class="elsevierStyleSimplePara elsevierViewall">The influences of Oxycodone &#40;OXY&#41; combined with Paclitaxel &#40;PTX&#41; on breast cancer cells are unclear&#46; The present study aimed to examine the effects of OXY combined with PTX on the proliferation&#44; apoptosis&#44; and migration of human breast cancer SKBR3 cells and the underlying mechanism&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Methods</span><p id="spara009" class="elsevierStyleSimplePara elsevierViewall">The proliferation&#44; apoptosis and invasion of SKBR3 cells were assessed by CCK-8&#44; colony formation assay&#44; flowcytometric&#44; Transwell assay and scratch assays&#44; respectively&#46; In addition&#44; Western blotting was used to detect the expression of related proteins in these cells&#46; The autophagic bodies were observed under a transmission electron microscope&#46;</p></span> <span id="abss0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0005">Results</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; significantly inhibited the viability&#44; colony-forming&#44; migration&#44; and invasion of SKBR3 cells as compared to the control group&#46; Furthermore&#44; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; markedly induced the apoptosis of SKBR3 cells and the levels of apoptosis-related proteins&#46; In addition&#44; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; and PTX inhibited the proliferation of SKBR3 cells synergistically as compared to PTX group in vitro&#46; Moreover&#44; OXY &#40;0&#46;25&#44; 0&#46;5 and 1 mM&#41; significantly elevated the PTX-induced apoptosis in SKBR3 cells via downregulating the expression of N-cadherin&#44; Becline-1 LC3-&#8545;&#44; p-Akt and p-mTOR and upregulating E-cadherin expression&#46; Compared with the control group&#44; OXY &#40;1 mM&#41; treatment induced autophagy in SKBR3 cells&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Conclusions</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">The present study indicates that OXY can enhance the antitumor effect of PTX on breast cancer in vitro&#46; Hence&#44; the combination of OXY with PTX may serve as a potential strategy for the treatment of breast cancer&#46;</p></span>"
        "secciones" => array:4 [
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            "titulo" => "Conclusions"
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          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">OXY inhibited the viability of SKBR3 cells and the combination of OXY with PTX synergistically inhibited the proliferation of SKBR3 cells&#46; &#40;A&#41; Cell viability was detected by CCK-8 assay in SKBR3 cells treated with OXY &#40;0&#46;025&#44; 0&#46;05&#44; 0&#46;1&#44; 0&#46;25&#44; 0&#46;5&#44; 1 and 2 mM&#41; for 24h and 48h&#46; &#42; p &#60; 0&#46;05 and &#94; p &#60; 0&#46;05 vs group C&#46; &#35; p &#60; 0&#46;05&#44; OXY &#40;0&#46;25&#44; 0&#46;1 mM&#41; group vs OXY &#40;0&#46;5 mM&#41; group&#46; &#40;B&#41; Cell viability was detected by CCK-8 assay in SKBR3 cells treated with PTX &#40;2&#44; 4&#44; 8&#44; 16&#44; 32 and 64 &#956;M&#41; for 24h&#46; &#42; p &#60; 0&#46;05 vs&#46; group P&#46; &#35; p &#60; 0&#46;05&#44; PTX &#40;2&#44; 8 &#956;M&#41; group vs&#46; PTX &#40;4 &#956;M&#41; group&#46; &#40;C&#41; Cell viability was detected by CCK-8 assay in SKBR3 cells treated with PTX &#40;8 &#956;M&#41; and OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; for 24h and 48h&#46; &#42; p &#60; 0&#46;05&#44; &#43; p &#60; 0&#46;05 vs&#46; group C&#46; &#35; p &#60; 0&#46;05&#44; &#94; p &#60; 0&#46;05 vs&#46; group P&#46; <span class="elsevierStyleSup">a</span> p &#60; 0&#46;05&#44; OXY &#40;0&#46;25&#44; 0&#46;1 mM&#41; group vs&#46; OXY &#40;0&#46;5 mM&#41; group&#46; <span class="elsevierStyleSup">b</span> p &#60; 0&#46;05&#44; P&#43;O 0&#46;25 group and P&#43;O 1 group vs&#46; P&#43;O 0&#46;25 group&#46; &#40;D&#41; Colony formation capability of SKBR3 cells was assessed after treatment with OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; for 48h&#44; and&#47;or PTX &#40;8 &#956;M&#41; for 24h&#46; &#42; p &#60; 0&#46;05 vs&#46; group C&#59; &#35; p &#60; 0&#46;05 vs&#46; group P&#46; At least three independent experiments in each group&#46; Abbreviations&#58; P&#44; Paclitaxel&#59; C&#44; Control&#59; O&#44; Oxycodone&#46;</p>"
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          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">OXY inhibited the migration and invasion of SKBR3 cells and the combination of OXY with PTX synergistically promoted these effects on SKBR3 cells&#46; &#40;A&#41; The migration and invasion of SKBR3 cells were detected by Transwell assay after treatment with oxycodone &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; for 48h&#46; &#40;B&#41; Combination of OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; with PTX synergistically inhibited the migration and invasion of SKBR3 cells within 24h&#46; &#40;C&#41; The migration and invasion of SKBR3 cells were detected by wound scratch assay after treatment with OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; for 48h&#46; &#40;D&#41; The migration and invasion of SKBR3 cells was detected by wound scratch assay after treatment with OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; and PTX for 24h&#46; &#42; p &#60; 0&#46;05 vs&#46; group C and P&#46; &#35; p &#60; 0&#46;05 vs&#46; group P&#46; &#35; p &#60; 0&#46;05&#44; O 0&#46;25 group and O 1 group vs&#46; O 0&#46;5 group&#44; P&#43; O 0&#46;25 group and P&#43; O 1 group vs&#46; P&#43; O 0&#46;25 group&#46; At least three independent experiments in each group&#46; Abbreviation&#58; P&#44; Paclitaxel&#59; C&#44; Control&#59; O&#44; Oxycodone&#46;</p>"
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          "en" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">OXY enhanced PTX-induced apoptosis in SKBR3 cells&#46; &#40;A&#41; Cells were treated with OXY &#40;0&#46;25&#44; 0&#46;5&#44; 1 mM&#41; for 48h&#44; and with OXY plus PTX &#40;8 &#956;M&#41; for 24h&#46; Apoptotic cells were detected after Annexin V and PI double staining&#46; The apoptotic rate was calculated&#46; &#42; p &#60; 0&#46;05 vs&#46; group C and P&#46; &#40;B&#41; The expression of apoptosis-related proteins &#40;Bcl-2 and Bax&#41; was detected by Western blotting&#46; &#42; p &#60; 0&#46;05 vs&#46; group C and P&#46; &#35; p &#60; 0&#46;05&#44; O 0&#46;25 group and O 1 group vs&#46; O 0&#46;5 group&#44; P&#43; O 0&#46;25 group and P&#43; O 1 group vs&#46; P&#43; O 0&#46;25 group&#46; At least three independent experiments in each group&#46; Abbreviation&#58; P&#44; Paclitaxel&#59; C&#44; Control&#59; O&#44; Oxycodone&#46;</p>"
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          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">OXY and OXY plus PTX inhibited EMT in SKBR3 cells&#46; The expression of EMT-related proteins &#40;D-cadherin and E-cadherin&#41; was detected by Western blotting&#46; &#42; p &#60; 0&#46;05 vs&#46; group C and P&#46; &#35; p &#60; 0&#46;05&#44; O 0&#46;25 group and O 1 group vs&#46; O 0&#46;5 group&#44; P&#43; O 0&#46;25 group and P&#43; O 1 group vs&#46; P&#43; O 0&#46;25 group&#46; At least three independent experiments in each group&#46; Abbreviation&#58; P&#44; paclitaxel&#59; C&#44; control&#59; O&#44; oxycodone&#46;</p>"
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          "en" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">OXY and the combination of OXY with PTX upregulated the expression of autophagy-related proteins and decreased the expression of PI3K&#47;AKT&#47;mTOR-related proteins in SKBR3 cells&#46; &#40;A&#41; The expression of PI3K&#47;AKT&#47;mTOR signaling pathway related proteins &#40;p-AKT and p-mTOR&#41; was detected by Western blotting after different treatments&#46; &#40;B&#41; The expression of autophagy-related proteins &#40;LC3-&#8545;and Becline-1&#41; was detected by Western blotting after different treatments&#46; &#42; p &#60; 0&#46;05 vs&#46; group C and P&#46; &#35; p &#60; 0&#46;05&#44; O 0&#46;25 group and O 1 group vs&#46; O 0&#46;5 group&#44; P&#43; O 0&#46;25 group and P&#43; O 1 group vs&#46; P&#43; O 0&#46;25 group&#46; At least three independent experiments in each group&#46; Abbreviation&#58; P&#44; Paclitaxel&#59; C&#44; Control&#59; O&#44; Oxycodone&#46;</p>"
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          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">OXY and the combination of OXY with PTX promoted autophagy in SKBR3 cells &#40;TEM&#41;&#46; Red arrow&#58; autophagic bodies&#46; Abbreviation&#58; P&#44; Paclitaxel&#59; C&#44; Control&#59; O&#44; Oxycodone&#46;</p>"
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      "titulo" => "References"
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