Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative bre...Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.展开更多
Triple-negative breast cancer(TNBC)has a poor prognosis because of its aggressive behavior,absence of specific therapies,and high recurrence.1 The exact molecular mechanisms that drive the progression of TNBC are not ...Triple-negative breast cancer(TNBC)has a poor prognosis because of its aggressive behavior,absence of specific therapies,and high recurrence.1 The exact molecular mechanisms that drive the progression of TNBC are not yet fully understood,thus highlighting the urgent need for discovering novel potential treatment targets.展开更多
新辅助化疗(neoadjuvant chemotherapy,NAC)通过缩小肿瘤、降低分期^([1]),已成为局部晚期和三阴性乳腺癌(triple negative breast cancer,TNBC)的标准治疗方案^([1])。这些治疗方案使不能手术的患者能够接受手术方式的治疗,或者使可手...新辅助化疗(neoadjuvant chemotherapy,NAC)通过缩小肿瘤、降低分期^([1]),已成为局部晚期和三阴性乳腺癌(triple negative breast cancer,TNBC)的标准治疗方案^([1])。这些治疗方案使不能手术的患者能够接受手术方式的治疗,或者使可手术的患者能够从乳房切除术转换为保乳治疗^([2])。通过评估NAC的疗效,可以判断肿瘤对当前治疗方案的反应;如果疗效不佳,可及时调整治疗方案,避免无效治疗对患者的进一步伤害。展开更多
Objectives:Drug resistance is the major determinant of chemotherapy failure,leading to relapse and tumor progression,demonstrating the urgent need for novel antineoplastic drugs.This study aimed to evaluate the antica...Objectives:Drug resistance is the major determinant of chemotherapy failure,leading to relapse and tumor progression,demonstrating the urgent need for novel antineoplastic drugs.This study aimed to evaluate the anticancer potential of two novel pyrazole derivatives,P3C.1 and P3C.2,and to elucidate their mechanism of action in cancer cells.Methods:The cytotoxicity of the compounds was evaluated across 27 different cancer cell lines via a nuclear staining assay.Subsequent flow cytometric and biochemical analyses were performed to assess reactive oxygen species(ROS)generation,apoptosis induction,mitochondrial integrity,and cell cycle progression.Additional studies included transcriptome analyses and immunoassays to characterize the molecular mechanisms underlying drug activity.Results:Two novel pyrazole derivatives,P3C.1 and P3C.2,were identified with potent cytotoxicity on a variety of cancer cell lines.Among the adherent cell lines tested,the triple-negative breast cancer(TNBC)cell line MDA-MB-231 exhibited the highest sensitivity to both compounds and was therefore selected for further experimentation.In vitro assays demonstrated that both compounds induced ROS generation,mitochondrial membrane depolarization,cell cycle arrest and apoptosis.Whole-transcriptome sequencing of P3C.1 and P3C.2-treated MDA-MB-231 and two lymphoblastic leukemia cell lines revealed four genes in common associated with cell signaling and membrane dynamics.Connectivity Map(CMAP)database comparisons of shared genes for each cancer subtype revealed a strong similarity between the two compounds with tubulin inhibitors,and subsequent assays confirmed that these compounds act as microtubule-disrupting agents.Moreover,protein phosphorylation analysis indicated that both compounds induced hyperphosphorylation of JNK,and ERK1/2,along with hypophosphorylation of p38 kinases.Conclusions:P3C.1 and P3C.2 emerged as promising anti-breast cancer agents with dual mechanisms of action involving microtubule disruption and altered kinase signaling,leading to induction of apoptosis.展开更多
三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学...三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。展开更多
目的:研究追毒方对三阴性乳腺癌细胞MDA-MB-231增殖、侵袭迁移的影响,并阐述其分子机制。方法:首先采用MTT细胞毒性试验,Transwell小室侵袭试验和伤口愈合试验观察不同浓度追毒方对三阴性乳腺癌细胞增殖及侵袭迁移能力的影响;通过流式...目的:研究追毒方对三阴性乳腺癌细胞MDA-MB-231增殖、侵袭迁移的影响,并阐述其分子机制。方法:首先采用MTT细胞毒性试验,Transwell小室侵袭试验和伤口愈合试验观察不同浓度追毒方对三阴性乳腺癌细胞增殖及侵袭迁移能力的影响;通过流式细胞术和乳酸试剂盒评估不同浓度追毒方处理后三阴性乳腺癌细胞糖摄取及乳酸生成、外排水平,以观察其有氧糖酵解水平;Western blot法检测追毒方对三阴性乳腺癌细胞的细胞外基质金属蛋白酶诱导因子(CD147)糖基化及葡萄糖转运蛋白(GLUT1)、单羧酸转运蛋白(MCT4)表达的影响;为了进一步证明追毒方对TNBC细胞有氧糖酵解的调控与CD147糖基化有关,使用糖基转移酶GnT-V激动剂处理细胞,观察其对追毒方抑制效应的逆转作用。结果:与空白对照组相比,追毒方0.1、0.2、0.4、0.8、1.6、3.2μg/mL组的细胞增殖活性显著降低(P<0.01),24 h IC_(50)为5.00μg/mL,48 h IC_(50)为0.25μg/mL,72 h IC_(50)为0.02μg/mL,追毒方0.4、0.8、1.6μg/mL组和2-DG 2101μg/mL组的侵袭能力和迁移能力显著降低,CD147糖基化水平显著下降(P<0.01),糖摄取能力显著降低(P<0.01),细胞内和培养上清的乳酸含量显著降低(P<0.01),有氧糖酵解关键跨膜蛋白GLUT1/MCT4的表达显著下调(P<0.01)。视黄酸处理模型中,与空白对照组相比,视黄酸30μg/mL组的糖摄取能力、细胞内及培养上清乳酸含量,CD147糖基化水平降低,GLUT1/MCT4的表达明显上调(P<0.05或P<0.01);与追毒方0.8μg/mL组相比,视黄酸30μg/mL组+追毒方0.8μg/mL组的上述检测指标明显上调(P<0.05或P<0.01)。结论:追毒方通过调控CD147糖基化抑制GLUT1、MCT4表达,从而下调三阴性乳腺癌有氧糖酵解葡萄糖通量及乳酸生成和外排,最终抑制三阴性乳腺癌增殖及侵袭迁移。展开更多
Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its liga...Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.展开更多
Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and...Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.展开更多
Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side ...Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.展开更多
基金the projects of the National Key Research and Development Program(No.2021YFA0716702)the National Natural Science Foundation of China(Nos.61805122,22022404 and 22074050)+5 种基金Green Industry Science and Technology Leading Project of Hubei University of Technology(No.XJ2021003301)the National Natural Science Foundation of Hubei Province(No.2022CFA033)supported by Chinese Society of Clinical Oncology(CSCO)supported by Jiangsu Hengrui Cancer Research Foundation(No.YHR2019–0325)supported by the Fundamental Research Funds for the Central Universities(No.CCNU22QN007)supported by the Opening Fund from the Jiangsu Key Laboratory of Medical Optics,Suzhou Institute of Biomedical Engineering and Technology(No.JKLMO202203)supported by the Key Laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science,MO(No.M2022–5).
文摘Immune checkpoint inhibitors(ICIs)therapy targeting programmed cell death ligand 1(PD-L1)and programmed death protein 1(PD-1)had exhibited significant clinical benefits for cancer treatment such as triple negative breast cancer(TNBC).However,the relatively low anti-tumor immune response rate and ICIs drug resistance highlight the necessity of developing ICIs combination therapy strategies to improve the anti-tumor effect of immunotherapy.Herein,the immunomodulator epigallocatechin gallate palmitate(PEGCG)and the immunoadjuvant metformin(MET)self-assembled into tumor-targeted micelles via hydrogen bond and electrostatic interaction,which encapsulated the therapeutic agents doxorubicin(DOX)-loaded PEGCG-MET micelles(PMD)and combined with ICIs(anti-PD-1 antibody)as therapeutic strategy to reduce the endogenous expression of PD-L1 and improve the tumor immunosuppressive microenvironment.The results presented that PMD integrated chemotherapy and immunotherapy to enhance antitumor efficacy in vitro and in vivo,compared with DOX or anti-PD-1 antibody for the therapy of TNBC.PMD micelles might be a potential candidate,which could remedy the shortcomings of antibody-based ICIs and provide synergistic effect to enhance the antitumor effects of ICIs in tumor therapy.
基金supported by the National Natural Science Foundation of China(No.82072923,82102829)Zhejiang Provincial Medical Science and Technology Program(China)(No.2020KY903).
文摘Triple-negative breast cancer(TNBC)has a poor prognosis because of its aggressive behavior,absence of specific therapies,and high recurrence.1 The exact molecular mechanisms that drive the progression of TNBC are not yet fully understood,thus highlighting the urgent need for discovering novel potential treatment targets.
文摘新辅助化疗(neoadjuvant chemotherapy,NAC)通过缩小肿瘤、降低分期^([1]),已成为局部晚期和三阴性乳腺癌(triple negative breast cancer,TNBC)的标准治疗方案^([1])。这些治疗方案使不能手术的患者能够接受手术方式的治疗,或者使可手术的患者能够从乳房切除术转换为保乳治疗^([2])。通过评估NAC的疗效,可以判断肿瘤对当前治疗方案的反应;如果疗效不佳,可及时调整治疗方案,避免无效治疗对患者的进一步伤害。
基金supported by NIH grant 1R16GM149379 to Renato J.Aguilerasupported by the core facilities of the BBRC,funded by the Research Centers in Minority Institutions grant 5U54MD007592 from the National Institute on Minority Health and Health Disparities to Robert A.Kirkensupported Denisse A.Gutierrez,Ana P.Betancourt,Elisa Robles-Escajeda and Armando Varela-Ramirez。
文摘Objectives:Drug resistance is the major determinant of chemotherapy failure,leading to relapse and tumor progression,demonstrating the urgent need for novel antineoplastic drugs.This study aimed to evaluate the anticancer potential of two novel pyrazole derivatives,P3C.1 and P3C.2,and to elucidate their mechanism of action in cancer cells.Methods:The cytotoxicity of the compounds was evaluated across 27 different cancer cell lines via a nuclear staining assay.Subsequent flow cytometric and biochemical analyses were performed to assess reactive oxygen species(ROS)generation,apoptosis induction,mitochondrial integrity,and cell cycle progression.Additional studies included transcriptome analyses and immunoassays to characterize the molecular mechanisms underlying drug activity.Results:Two novel pyrazole derivatives,P3C.1 and P3C.2,were identified with potent cytotoxicity on a variety of cancer cell lines.Among the adherent cell lines tested,the triple-negative breast cancer(TNBC)cell line MDA-MB-231 exhibited the highest sensitivity to both compounds and was therefore selected for further experimentation.In vitro assays demonstrated that both compounds induced ROS generation,mitochondrial membrane depolarization,cell cycle arrest and apoptosis.Whole-transcriptome sequencing of P3C.1 and P3C.2-treated MDA-MB-231 and two lymphoblastic leukemia cell lines revealed four genes in common associated with cell signaling and membrane dynamics.Connectivity Map(CMAP)database comparisons of shared genes for each cancer subtype revealed a strong similarity between the two compounds with tubulin inhibitors,and subsequent assays confirmed that these compounds act as microtubule-disrupting agents.Moreover,protein phosphorylation analysis indicated that both compounds induced hyperphosphorylation of JNK,and ERK1/2,along with hypophosphorylation of p38 kinases.Conclusions:P3C.1 and P3C.2 emerged as promising anti-breast cancer agents with dual mechanisms of action involving microtubule disruption and altered kinase signaling,leading to induction of apoptosis.
文摘三阴性乳腺癌(triple negative breast cancer,TNBC)因其分化程度低、发病年龄小、复发风险高、极易出现耐药、临床预后差且缺乏特定的治疗靶点,一直是乳腺癌治疗及研究中的难点、热点问题,同时其对应的研究学方法层出不穷。蛋白质组学作为高特异性及灵敏性的高通量研究方法,逐步成为目前应用热点。本文旨在从转化医学的角度分析蛋白质组学方法在TNBC诊疗研究中的临床应用价值。
文摘目的:研究追毒方对三阴性乳腺癌细胞MDA-MB-231增殖、侵袭迁移的影响,并阐述其分子机制。方法:首先采用MTT细胞毒性试验,Transwell小室侵袭试验和伤口愈合试验观察不同浓度追毒方对三阴性乳腺癌细胞增殖及侵袭迁移能力的影响;通过流式细胞术和乳酸试剂盒评估不同浓度追毒方处理后三阴性乳腺癌细胞糖摄取及乳酸生成、外排水平,以观察其有氧糖酵解水平;Western blot法检测追毒方对三阴性乳腺癌细胞的细胞外基质金属蛋白酶诱导因子(CD147)糖基化及葡萄糖转运蛋白(GLUT1)、单羧酸转运蛋白(MCT4)表达的影响;为了进一步证明追毒方对TNBC细胞有氧糖酵解的调控与CD147糖基化有关,使用糖基转移酶GnT-V激动剂处理细胞,观察其对追毒方抑制效应的逆转作用。结果:与空白对照组相比,追毒方0.1、0.2、0.4、0.8、1.6、3.2μg/mL组的细胞增殖活性显著降低(P<0.01),24 h IC_(50)为5.00μg/mL,48 h IC_(50)为0.25μg/mL,72 h IC_(50)为0.02μg/mL,追毒方0.4、0.8、1.6μg/mL组和2-DG 2101μg/mL组的侵袭能力和迁移能力显著降低,CD147糖基化水平显著下降(P<0.01),糖摄取能力显著降低(P<0.01),细胞内和培养上清的乳酸含量显著降低(P<0.01),有氧糖酵解关键跨膜蛋白GLUT1/MCT4的表达显著下调(P<0.01)。视黄酸处理模型中,与空白对照组相比,视黄酸30μg/mL组的糖摄取能力、细胞内及培养上清乳酸含量,CD147糖基化水平降低,GLUT1/MCT4的表达明显上调(P<0.05或P<0.01);与追毒方0.8μg/mL组相比,视黄酸30μg/mL组+追毒方0.8μg/mL组的上述检测指标明显上调(P<0.05或P<0.01)。结论:追毒方通过调控CD147糖基化抑制GLUT1、MCT4表达,从而下调三阴性乳腺癌有氧糖酵解葡萄糖通量及乳酸生成和外排,最终抑制三阴性乳腺癌增殖及侵袭迁移。
基金supported by the Department of Science and Technology(Nano Mission:DST/NM/NT/2018/105(G),SERB:EMR/2017/000992/HS&EMR/2017/001183)Council of Scientific and Industrial Research[(FBR Project No.31-2(274)2020e21),HCP-40],Govt.of India.
文摘Maintaining the balance between eliciting immune responses against foreign pro-teins and tolerating self-proteins is crucial for maintenance of homeostasis.The functions of programmed death protein 1(PD-1)and its ligand programmed death ligand 1(PD-L1)are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells.However,cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation.Over the past few years’rapid development in cancer immunotherapy has opened a new avenue in cancer treatment.Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy.Initially,immune checkpoint monotherapies were not very successful,making breast cancer less immunogenic.Although,recent reports support the presence of tumor infiltrating lympho-cytes(TILs)in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy,which is effective in PD-L1 positive patients.Recently,anti-PD-1(pembrolizumab)and anti-PD-L1(atezolizumab)gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research.Likewise,this article gathered understand-ing of PD-1 and PD-L1 in recent years,their signaling networks,interaction with other mole-cules,regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy.Additionally,authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.
基金The study was supported by Ovarian Cancer Research Alliance and the Johns Hopkins-Allegheny Health Network Cancer Research Fund,United States.
文摘Reprogramming of metabolic pathways,a hallmark of human cancer,results from a process in which cancer cells become dependent on specific metabolic pathways such as glutamine catabolism or glutaminolysis for growth and survival.Previous studies have demonstrated that triplenegative breast cancers(TNBC)may use glutamine as an extracellular nutrient source to generate lipids,proteins,and nucleic acids.1 Glutamine catabolism in cancer cells also contributes to the production of the antioxidant,glutathione(GSH),which is critical for redox homeostasis and for protection of cells from oxidative stress elicited by reactive oxygen species(ROS).2 Considering TNBC cell lines are often dependent on glutamine for growth and survival,we sought to determine whether targeting glutaminolysis with a small molecule inhibitor,CB-839,in combination with platinum-based chemotherapy drug,would elicit significant anti-tumor activity.
基金the Xuzhou Science and Technology Bureau,No.KC23186,Jiangsu Provincial Key Laboratory of New Drug Research and Clinical Pharmacy Project(No.XZSYSKF2023013)Key Medical Disciplines of Jiangsu Province’s 14th Five-Year Plan(ZDXK202237).
文摘Background:Cisplatin(DDP)has been used in the treatment of various human cancers.However,DDP alone lacks efficacy in treating triple-negative breast cancer(TNBC),and its clinical application is often hampered by side effects.Astragalus polysaccharide(APS)is one of the active components extracted from Astragalus membranaceus and has gained attention for its various biological properties.This research is aimed to evaluate the effectiveness of a combination of APS and DDP on TNBC and explore the potential mechanisms.Methods:The efficacy and mechanisms of single or combined treatment were evaluated using Cell Counting Kit-8(CCK8)assay,Annexin V-fluorescein isothiocyanate(FITC)/propidium iodide(PI)staining,wound healing assay,trans-well invasion/migration assay,hematoxylin-eosin(HE)staining,immunohistochemical(IHC)staining,Western Blot(WB)analysis,and fluorescence-activated cell sorting(FACS).An orthotopic model of TNBC was used to assess the in vivo treatment efficacy of single or combination treatment.Results:APS significantly enhanced the anti-proliferative,anti-migratory,and anti-invasive effects of DDP on TNBC cells.The combination of APS and DDP downregulated anti-apoptotic genes(Bcl2 and Bcl-xL)while upregulating pro-apoptotic genes(Puma,Cle-Caspase3,Cle-PARP),leading to enhanced apoptosis.This combination treatment increased E-cadherin levels,decreased Vimentin,Snail,Slug,and Twist levels,and effectively suppressed epithelial-mesenchymal transition(EMT)-associated cell invasion.In the orthotopic model of TNBC,a synergistic reduction in tumor growth was observed in mice treated with APS and DDP.Additionally,the combination of APS and DDP induced the infiltration of CD8+T lymphocytes into the tumor immune microenvironment.Conclusion:The combination of APS and DDP exhibits more potent tumor inhibition and anti-tumor immunity than either agent alone,representing a novel approach to enhance therapeutic efficacy without increasing the side effects of DDP.
