Jiaji Yue, Zhe-Sheng Chen, Xiang-Xi Xu, Shenglong Li
Osteosarcoma is a primary malignant tumor of the skeleton with the morbidity of 2.5 in 1 million. The regularly on-set is in the epiphysis of the extremities with a high possibility of early metastasis, rapid progression, and poor prognosis. The survival rate of patients with metastatic or recurrent osteosarcoma remains low, and novel diagnostic and therapeutic methods are urgently needed. Exosomes are extracellular vesicles 30-150 nm in diameter secreted by various cells that are widely present in various body fluids. Exosomes are abundant in biologically active components such as proteins, nucleic acids, and lipids. Exosomes participate in numerous physiological and pathological processes via intercellular substance exchange and signaling. This review presents the novel findings of exosomes in osteosarcoma in diagnosis, prognosis, and therapeutic aspects.
{"title":"Functions and therapeutic potentials of exosomes in osteosarcoma.","authors":"Jiaji Yue, Zhe-Sheng Chen, Xiang-Xi Xu, Shenglong Li","doi":"10.15212/amm-2022-0024","DOIUrl":"https://doi.org/10.15212/amm-2022-0024","url":null,"abstract":"<p><p>Osteosarcoma is a primary malignant tumor of the skeleton with the morbidity of 2.5 in 1 million. The regularly on-set is in the epiphysis of the extremities with a high possibility of early metastasis, rapid progression, and poor prognosis. The survival rate of patients with metastatic or recurrent osteosarcoma remains low, and novel diagnostic and therapeutic methods are urgently needed. Exosomes are extracellular vesicles 30-150 nm in diameter secreted by various cells that are widely present in various body fluids. Exosomes are abundant in biologically active components such as proteins, nucleic acids, and lipids. Exosomes participate in numerous physiological and pathological processes via intercellular substance exchange and signaling. This review presents the novel findings of exosomes in osteosarcoma in diagnosis, prognosis, and therapeutic aspects.</p>","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 4","pages":"552-562"},"PeriodicalIF":0.0,"publicationDate":"2022-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879305/pdf/nihms-1863627.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9157461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Current anticancer treatments have many limitations to achieving high efficacy. Hence, novel strategies that broaden therapeutic prospects must urgently be developed. Ferroptosis is an iron-dependent form of non-apoptotic programmed cell death that is induced by cellular antioxidative system inhibition. Photodynamic therapy (PDT) uses photosensitizers to generate reactive oxygen species and aggravate oxidative stress in tumor cells. Combining ferroptosis with PDT cooperatively regulates intracellular redox homeostasis, thus increasing cancer cell susceptibility to oxidative stress and yielding synergistic anticancer effects. In this review, various strategies for combining ferroptosis with PDT are comprehensively summarized and discussed, including mono-PDT and PDT-induced ferroptosis, combining PDT with small-molecule ferroptosis inducers, and combining PDT with metal-ion-induced ferroptosis. Additionally, the possibility of combining ferroptosis and PDT with other anti-tumor therapies is discussed. Finally, the prospects and challenges of combining ferroptosis with PDT in clinical cancer treatment are addressed. With increased understanding of the superiority of combination PDT with ferroptosis for cancer treatment, we hope that drug delivery systems based on this strategy will be further developed to increase anticancer efficiency and achieve successful clinical translation.
{"title":"Recent progress in cancer therapy based on the combination of ferroptosis with photodynamic therapy","authors":"Zeping Gao, Shunzhe Zheng, K. Kamei, Chutong Tian","doi":"10.15212/amm-2022-0025","DOIUrl":"https://doi.org/10.15212/amm-2022-0025","url":null,"abstract":"Current anticancer treatments have many limitations to achieving high efficacy. Hence, novel strategies that broaden therapeutic prospects must urgently be developed. Ferroptosis is an iron-dependent form of non-apoptotic programmed cell death that is induced by cellular antioxidative system inhibition. Photodynamic therapy (PDT) uses photosensitizers to generate reactive oxygen species and aggravate oxidative stress in tumor cells. Combining ferroptosis with PDT cooperatively regulates intracellular redox homeostasis, thus increasing cancer cell susceptibility to oxidative stress and yielding synergistic anticancer effects. In this review, various strategies for combining ferroptosis with PDT are comprehensively summarized and discussed, including mono-PDT and PDT-induced ferroptosis, combining PDT with small-molecule ferroptosis inducers, and combining PDT with metal-ion-induced ferroptosis. Additionally, the possibility of combining ferroptosis and PDT with other anti-tumor therapies is discussed. Finally, the prospects and challenges of combining ferroptosis with PDT in clinical cancer treatment are addressed. With increased understanding of the superiority of combination PDT with ferroptosis for cancer treatment, we hope that drug delivery systems based on this strategy will be further developed to increase anticancer efficiency and achieve successful clinical translation.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46883262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoyan Xu, Renjie Li, Runqi Dong, Yan-fang Yang, Hongliang Wang, Jia Hua Cheng, Yuling Liu, Jun Ye
Tumor-associated macrophages (TAMs) are key contributors to tumor development, accelerated tumor invasion and metastasis, and induction of immunosuppression. Targeted delivery of immunomodulatory agents to promote polarization of TAMs may alleviate the immunosuppressive tumor microenvironment. Calcium carbonate nanoparticles (CCN), which exhibit excellent biocompatibility, pH sensitivity, and easy surface modification, have attracted substantial attention in targeted nano delivery. In this study, CCN were used as a matrix material to develop UNO-peptide-modified lipid CCN for targeted immunomodulation of TAMs by using the mannose receptor overexpressed on the surfaces of TAMs as targets. The preparation of CCN was optimized through single-factor testing with the gas diffusion method with the particle size as the index. The surface modification of CCN with UNO-peptide-modified phospholipids was performed, and its targeting effect on TAMs was investigated. The average particle size of the CCN and UNO-peptide-modified CCN was 144.5 ± 3.8 nm and 167.0 ± 1.3 nm, respectively. UNO-peptide-modified CCN entered TAMs via actively targeted uptake mediated by mannose receptors. Our results demonstrated that the developed UNO-peptide-modified CCN with controlled nano-size and excellent TAMs-targeting properties is a highly promising nanocarrier for targeted delivery of TAM immunomodulatory agents.
{"title":"In vitro characterization and cellular uptake profiles of TAMs-targeted lipid calcium carbonate nanoparticles for cancer immunotherapy","authors":"Xiaoyan Xu, Renjie Li, Runqi Dong, Yan-fang Yang, Hongliang Wang, Jia Hua Cheng, Yuling Liu, Jun Ye","doi":"10.15212/amm-2022-0030","DOIUrl":"https://doi.org/10.15212/amm-2022-0030","url":null,"abstract":"Tumor-associated macrophages (TAMs) are key contributors to tumor development, accelerated tumor invasion and metastasis, and induction of immunosuppression. Targeted delivery of immunomodulatory agents to promote polarization of TAMs may alleviate the immunosuppressive tumor microenvironment. Calcium carbonate nanoparticles (CCN), which exhibit excellent biocompatibility, pH sensitivity, and easy surface modification, have attracted substantial attention in targeted nano delivery. In this study, CCN were used as a matrix material to develop UNO-peptide-modified lipid CCN for targeted immunomodulation of TAMs by using the mannose receptor overexpressed on the surfaces of TAMs as targets. The preparation of CCN was optimized through single-factor testing with the gas diffusion method with the particle size as the index. The surface modification of CCN with UNO-peptide-modified phospholipids was performed, and its targeting effect on TAMs was investigated. The average particle size of the CCN and UNO-peptide-modified CCN was 144.5 ± 3.8 nm and 167.0 ± 1.3 nm, respectively. UNO-peptide-modified CCN entered TAMs via actively targeted uptake mediated by mannose receptors. Our results demonstrated that the developed UNO-peptide-modified CCN with controlled nano-size and excellent TAMs-targeting properties is a highly promising nanocarrier for targeted delivery of TAM immunomodulatory agents.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41783643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Na Li, Yanhong Zhang, Jing-wei Lv, Dazhong Sun, Jianan Lin, Qihang Pang, Hui Li, Zhanhong Cao, Yaxin Liu, Zhuguo Li, Xingyu Fang, Dianyu Li, Haonan Bai, Yuanyuan An, Jun Jiang, Rui Zhang, Qing Yang
Oxidative stress is an important pathogenic mechanism in degenerative diseases such as Alzheimer’s disease. Although ginsenoside compound K (CK) is protective against neuronal oxidative damage, the underlying mechanism remains to be understood. In this study, the protective effects of ginsenoside CK against oxidative stress damage induced by hydrogen peroxide in HT22 cells were investigated with 1H nuclear magnetic resonance (1H-NMR)-based metabolomics. The optimal CK concentration for decreasing oxidative stress damage in nerves was determined with MTT assays. CK (8 μM) significantly increased the HT22 cell survival rate after the model was established. Cell lysates were subjected to 1H-NMR metabolomics, western blotting, and ATP assays for verification. Metabolic perturbation occurred in HT22 cells in the model group but not the control group. Twenty biomarkers were identified and used to analyze metabolic pathways. CK reversed metabolic changes in HT22 cells by altering taurine, glutamate, glycine, and glutathione metabolism. Subsequently, CK increased ATP content and the expression of components of the PI3K/AKT signaling pathway in HT22 cells. These findings demonstrated that CK prevents oxidative stress damage and protects nerves by regulating energy-metabolism pathways, such as those of taurine, glutamate, and other amino acids, thus providing a rationale for the use of CK in Alzheimer’s disease treatment.
{"title":"Protective effects of ginsenoside CK against oxidative stress-induced neuronal damage, assessed with 1H-NMR-based metabolomics","authors":"Na Li, Yanhong Zhang, Jing-wei Lv, Dazhong Sun, Jianan Lin, Qihang Pang, Hui Li, Zhanhong Cao, Yaxin Liu, Zhuguo Li, Xingyu Fang, Dianyu Li, Haonan Bai, Yuanyuan An, Jun Jiang, Rui Zhang, Qing Yang","doi":"10.15212/amm-2022-0009","DOIUrl":"https://doi.org/10.15212/amm-2022-0009","url":null,"abstract":"Oxidative stress is an important pathogenic mechanism in degenerative diseases such as Alzheimer’s disease. Although ginsenoside compound K (CK) is protective against neuronal oxidative damage, the underlying mechanism remains to be understood. In this study, the protective effects of ginsenoside CK against oxidative stress damage induced by hydrogen peroxide in HT22 cells were investigated with 1H nuclear magnetic resonance (1H-NMR)-based metabolomics. The optimal CK concentration for decreasing oxidative stress damage in nerves was determined with MTT assays. CK (8 μM) significantly increased the HT22 cell survival rate after the model was established. Cell lysates were subjected to 1H-NMR metabolomics, western blotting, and ATP assays for verification. Metabolic perturbation occurred in HT22 cells in the model group but not the control group. Twenty biomarkers were identified and used to analyze metabolic pathways. CK reversed metabolic changes in HT22 cells by altering taurine, glutamate, glycine, and glutathione metabolism. Subsequently, CK increased ATP content and the expression of components of the PI3K/AKT signaling pathway in HT22 cells. These findings demonstrated that CK prevents oxidative stress damage and protects nerves by regulating energy-metabolism pathways, such as those of taurine, glutamate, and other amino acids, thus providing a rationale for the use of CK in Alzheimer’s disease treatment.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43068130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xue-wen Liu, Xin Jin, Hongling Ou, Chen Qian, Hui Wu, C. Zuo, Yuliang Ren, Miaoxin Fu, Te Zhang, Liang Zhang, Y. Si, Ying Liu
Signal transducer and activator of transcription 3 (STAT3) plays a key role in promoting tumor malignant progression. Suppression of hyperactivated STAT3 signaling has emerged as a potential therapeutic strategy for many cancer types. In this study, the effect of 6-ethoxydihydrosanguinarine (6-EDS), a secondary transformation product formed from dihydrosanguinarine, isolated from Macleaya (Papaveraceae), was evaluated in gastric cancer (GC). We demonstrated that 6-EDS inhibited the survival, migration, and invasiveness of GC cells in vitro. Moreover, 6-EDS inhibited STAT3 phosphorylation and transcriptional activity, thus suppressing the mRNA expression of downstream target genes associated with the malignant survival, migration, and invasiveness of GC cells. Molecular docking indicated that 6-EDS directly bound the SH2 domain of STAT3. Molecular dynamics simulations suggested that 6-EDS inhibited the binding of phosphorylated and non-phosphorylated STAT3 to target DNA. Cellular thermal-shift assays and microscale thermophoresis further confirmed the direct binding of 6-EDS to STAT3. Site-directed mutagenesis indicated that the S611 residue in the SH2 domain of STAT3 is critical for 6-EDS binding. In vivo, 6-EDS decreased tumor growth in xenografted nude mice by blocking STAT3 signaling. These findings indicated that 6-EDS, a direct STAT3 inhibitor, may be a potent anticancer candidate for GC therapy.
{"title":"The direct STAT3 inhibitor 6-ethoxydihydrosanguinarine exhibits anticancer activity in gastric cancer","authors":"Xue-wen Liu, Xin Jin, Hongling Ou, Chen Qian, Hui Wu, C. Zuo, Yuliang Ren, Miaoxin Fu, Te Zhang, Liang Zhang, Y. Si, Ying Liu","doi":"10.15212/amm-2022-0027","DOIUrl":"https://doi.org/10.15212/amm-2022-0027","url":null,"abstract":"Signal transducer and activator of transcription 3 (STAT3) plays a key role in promoting tumor malignant progression. Suppression of hyperactivated STAT3 signaling has emerged as a potential therapeutic strategy for many cancer types. In this study, the effect of 6-ethoxydihydrosanguinarine (6-EDS), a secondary transformation product formed from dihydrosanguinarine, isolated from Macleaya (Papaveraceae), was evaluated in gastric cancer (GC). We demonstrated that 6-EDS inhibited the survival, migration, and invasiveness of GC cells in vitro. Moreover, 6-EDS inhibited STAT3 phosphorylation and transcriptional activity, thus suppressing the mRNA expression of downstream target genes associated with the malignant survival, migration, and invasiveness of GC cells. Molecular docking indicated that 6-EDS directly bound the SH2 domain of STAT3. Molecular dynamics simulations suggested that 6-EDS inhibited the binding of phosphorylated and non-phosphorylated STAT3 to target DNA. Cellular thermal-shift assays and microscale thermophoresis further confirmed the direct binding of 6-EDS to STAT3. Site-directed mutagenesis indicated that the S611 residue in the SH2 domain of STAT3 is critical for 6-EDS binding. In vivo, 6-EDS decreased tumor growth in xenografted nude mice by blocking STAT3 signaling. These findings indicated that 6-EDS, a direct STAT3 inhibitor, may be a potent anticancer candidate for GC therapy.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43597903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiping Li, Y. Zu, Guodong Li, Dong Xiang, Chengliang Zhang, Dong Liu
Intrahepatic cholestasis (IC) is a liver disease caused by disorders in bile formation and excretion, owing to structural and functional abnormalities in hepatocytes and/or bile capillaries. IC is commonly caused by hepatitis virus, alcohol consumption, drug-induced liver damage, autoimmune liver disease and heredity. In the absence of effective treatment, IC can progress to liver fibrosis, cirrhosis and ultimately liver failure. However, the mechanisms underlying IC remain poorly understood. IC is believed to be closely associated with changes in the transcription, function and localization of hepatocellular transport proteins. To better understand the molecular mechanisms of transport proteins in IC, herein, we review the roles of these transport proteins and discuss their underlying regulatory mechanisms in IC. Our aim is to provide a reference for understanding IC pathogenesis and developing effective drug therapies.
{"title":"Molecular mechanisms of transporter regulation and their impairment in intrahepatic cholestasis","authors":"Xiping Li, Y. Zu, Guodong Li, Dong Xiang, Chengliang Zhang, Dong Liu","doi":"10.15212/amm-2022-0029","DOIUrl":"https://doi.org/10.15212/amm-2022-0029","url":null,"abstract":"Intrahepatic cholestasis (IC) is a liver disease caused by disorders in bile formation and excretion, owing to structural and functional abnormalities in hepatocytes and/or bile capillaries. IC is commonly caused by hepatitis virus, alcohol consumption, drug-induced liver damage, autoimmune liver disease and heredity. In the absence of effective treatment, IC can progress to liver fibrosis, cirrhosis and ultimately liver failure. However, the mechanisms underlying IC remain poorly understood. IC is believed to be closely associated with changes in the transcription, function and localization of hepatocellular transport proteins. To better understand the molecular mechanisms of transport proteins in IC, herein, we review the roles of these transport proteins and discuss their underlying regulatory mechanisms in IC. Our aim is to provide a reference for understanding IC pathogenesis and developing effective drug therapies.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43777270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gang Sheng, Na Tian, Huijuan Duan, Zhaogang Sun, Hong-qian Chu
Infectious lung diseases are inflammatory diseases of the lungs caused by infectious agents such as bacteria, viruses or fungi. Oral or intravenous administration of antibiotics is the most common method of treatment, but some drugs have poor release stability, high systemic toxicity and susceptibility to drug resistance. Nanodrug delivery systems are promising alternatives for the treatment of infectious lung diseases, because they provide the advantages of enhancing the stability and solubility of delivered drugs, increasing pulmonary accumulation, decreasing systemic toxicity and ameliorating drug resistance. This review provides a brief overview of recent advances in approaches and ideas in pulmonary drug delivery methods. We believe that nano-based therapeutic strategies offer great potential to broaden the scope of treatment of infectious lung diseases and enhance therapeutic efficacy.
{"title":"Advances in therapeutic nanodrug delivery systems for infectious lung diseases: a review","authors":"Gang Sheng, Na Tian, Huijuan Duan, Zhaogang Sun, Hong-qian Chu","doi":"10.15212/amm-2022-0019","DOIUrl":"https://doi.org/10.15212/amm-2022-0019","url":null,"abstract":"Infectious lung diseases are inflammatory diseases of the lungs caused by infectious agents such as bacteria, viruses or fungi. Oral or intravenous administration of antibiotics is the most common method of treatment, but some drugs have poor release stability, high systemic toxicity and susceptibility to drug resistance. Nanodrug delivery systems are promising alternatives for the treatment of infectious lung diseases, because they provide the advantages of enhancing the stability and solubility of delivered drugs, increasing pulmonary accumulation, decreasing systemic toxicity and ameliorating drug resistance. This review provides a brief overview of recent advances in approaches and ideas in pulmonary drug delivery methods. We believe that nano-based therapeutic strategies offer great potential to broaden the scope of treatment of infectious lung diseases and enhance therapeutic efficacy.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48422650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peng Chen, Zhao Cui, Caifeng Li, Shiwen Deng, Han Yang
Traditional protein chips are based on solid chips and cannot enable drug and target screening in a label-free manner. Herein, a protein thermal shift chip (PTSC) based on fluorescence signals is proposed, which enables low-cost, high-throughput, label-free screening. We developed a PTSC for COVID-19, containing 12 SARS-CoV-2 and host target proteins. A series of quality-control tests were performed for small-molecule drugs, macromolecular antibodies, and herbal-medicine extracts. This chip enabled high-throughput screening of COVID-19 drugs and thus may serve as a tool for screening drug targets clinically effective drugs.
{"title":"Establishment of a protein thermal shift chip (PTSC) for COVID-19 and exploration of the future of protein chips in pharmacology","authors":"Peng Chen, Zhao Cui, Caifeng Li, Shiwen Deng, Han Yang","doi":"10.15212/amm-2022-0016","DOIUrl":"https://doi.org/10.15212/amm-2022-0016","url":null,"abstract":"Traditional protein chips are based on solid chips and cannot enable drug and target screening in a label-free manner. Herein, a protein thermal shift chip (PTSC) based on fluorescence signals is proposed, which enables low-cost, high-throughput, label-free screening. We developed a PTSC for COVID-19, containing 12 SARS-CoV-2 and host target proteins. A series of quality-control tests were performed for small-molecule drugs, macromolecular antibodies, and herbal-medicine extracts. This chip enabled high-throughput screening of COVID-19 drugs and thus may serve as a tool for screening drug targets clinically effective drugs.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46971048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shi-Bing Zhang, M. Hong, Xiao-Yang Sun, Da-xiong Huang, Dan-hua He, Yu-Fei Chen, Yong Yuan, Yongqiang Liu
Silybin (SB), a natural flavonoid isolated from Silybum marianum, has been used to treat hepatic fibrosis in clinical settings and as a dietary supplement, because of its hepatoprotective potential. Numerous studies have shown that SB also exerts promising anticancer effects; however, the anticancer targets of SB and the underlying mechanism were unclear. Herein, we found that SB significantly inhibited the proliferation of non-small cell lung cancer without causing cytotoxicity toward normal Beas-2B bronchial epithelial cells. Mechanistically, SB binds the F-box protein Skp2 and disrupts Skp1-Skp2 interaction, thereby decreasing Skp2 protein levels, inducing accumulation of Skp2 substrates, and leading to G1-phase cell-cycle arrest and the suppression of cell migration. In lung orthotopic xenografts, SB also significantly decreased Skp2 expression and increased p27/Kip1 protein levels. SB administration inhibited tumor growth and metastasis in lung tissue, thus prolonging survival time in mice without causing obvious toxicity. Thus, SB is a potential Skp2-targeting agent that warrants further clinical investigation.
{"title":"Silybin has therapeutic efficacy against non-small cell lung cancer through targeting of Skp2","authors":"Shi-Bing Zhang, M. Hong, Xiao-Yang Sun, Da-xiong Huang, Dan-hua He, Yu-Fei Chen, Yong Yuan, Yongqiang Liu","doi":"10.15212/amm-2022-0011","DOIUrl":"https://doi.org/10.15212/amm-2022-0011","url":null,"abstract":"Silybin (SB), a natural flavonoid isolated from Silybum marianum, has been used to treat hepatic fibrosis in clinical settings and as a dietary supplement, because of its hepatoprotective potential. Numerous studies have shown that SB also exerts promising anticancer effects; however, the anticancer targets of SB and the underlying mechanism were unclear. Herein, we found that SB significantly inhibited the proliferation of non-small cell lung cancer without causing cytotoxicity toward normal Beas-2B bronchial epithelial cells. Mechanistically, SB binds the F-box protein Skp2 and disrupts Skp1-Skp2 interaction, thereby decreasing Skp2 protein levels, inducing accumulation of Skp2 substrates, and leading to G1-phase cell-cycle arrest and the suppression of cell migration. In lung orthotopic xenografts, SB also significantly decreased Skp2 expression and increased p27/Kip1 protein levels. SB administration inhibited tumor growth and metastasis in lung tissue, thus prolonging survival time in mice without causing obvious toxicity. Thus, SB is a potential Skp2-targeting agent that warrants further clinical investigation.","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67303275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang
Inhibition or degradation of anti-apoptotic protein BCL-XL is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-XL, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-XL PROTACs using MDM2 as E3 ligase for degradation of BCL-XL. Three MDM2-BCL-XL PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-XL inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCL-XL and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.
{"title":"MDM2-BCL-X<sub>L</sub> PROTACs enable degradation of BCL-X<sub>L</sub> and stabilization of p53.","authors":"Mengyang Chang, Feng Gao, Jing Chen, Giri Gnawali, Wei Wang","doi":"10.15212/amm-2022-0022","DOIUrl":"https://doi.org/10.15212/amm-2022-0022","url":null,"abstract":"<p><p>Inhibition or degradation of anti-apoptotic protein BCL-X<sub>L</sub> is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X<sub>L</sub>, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X<sub>L</sub> PROTACs using MDM2 as E3 ligase for degradation of BCL-X<sub>L</sub>. Three MDM2-BCL-X<sub>L</sub> PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X<sub>L</sub> inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found <b>BMM4</b> exhibited potent, selective degradation activity against BCL-X<sub>L</sub> and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.</p>","PeriodicalId":72055,"journal":{"name":"Acta materia medica","volume":"1 3","pages":"333-342"},"PeriodicalIF":0.0,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004178/pdf/nihms-1833345.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9106039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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