Pub Date : 2024-01-01DOI: 10.2174/1568009623666230818151830
Qiang Liang, Bing Wang, Chenran Zhang, Chaoli Song, Junyu Wang, Wei Sun, Lei Jiang, Jing Lin
Background: Chemoresistance in gliomas accounts for the major cause of tumor progress and recurrence during comprehensive treatment with alkylating agents including temozolomide (TMZ). The oncogenic role of Enhancer of zeste homolog 2 (EZH2) has been identified in many solid malignancies including gliomas, though the accurate effect of EZH2 on chemotherapy resistance of gliomas has been elusive.
Objective: To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms.
Methods: Immunohistochemistry (IHC) and Reverse transcription-quantitative (RT-q) PCR, and western blot assay were performed for expressional analysis. Cell Counting Kit-8 (CCK-8) assay was applied to determine the TMZ sensitivity. EZH2-silencing lentivirus was generated for mechanic study.
Results: EZH2 was overexpressed in gliomas both at the transcriptional and protein levels. EZH2 level in glioma cell lines was positively correlated with resistance to TMZ, represented by the 50% inhibition rate (IC50). Moreover, there was increased TMZ sensitivity in EZH2-inhibited glioma cells than in the control cells. Furthermore, we determined that PARP1 was a common molecule among the downregulated DNA repair proteins in both U251 and U87 glioma cell lines after EZH2 inhibition. Specifically, we observed a spontaneous increase of PARP1 expression with TMZ treatment and interestingly, the increase of PARP1 could be also reduced by EZH2 inhibition in the glioma cells. Finally, combined treatment with lentivirus-induced EZH2 inhibition and a PARP1 inhibitor dramatically enhanced TMZ cytotoxicity compared with either one alone.
Conclusion: EZH2-PARP-1 signaling axis is possibly responsible for the chemoresistance of gliomas to TMZ. Simultaneously inhibiting these two genes may improve the outcome of TMZ chemotherapy.
背景:在使用包括替莫唑胺(TMZ)在内的烷化剂进行综合治疗期间,胶质瘤的化疗耐药性是导致肿瘤进展和复发的主要原因。在包括胶质瘤在内的多种实体瘤恶性肿瘤中,泽斯特同源增强子2(Enhancer of zeste homolog 2,EZH2)的致癌作用已被确认,但EZH2对胶质瘤化疗耐药性的确切影响一直难以捉摸:阐明EHZ2对胶质瘤TMZ耐药的作用及其分子机制:方法:对EHZ2进行免疫组织化学(IHC)、逆转录定量(RT-q)PCR和Western印迹分析。细胞计数试剂盒-8(CCK-8)检测用于确定TMZ的敏感性。在机理研究中生成了EZH2沉默慢病毒:结果:EZH2在胶质瘤中的转录水平和蛋白水平均过表达。脑胶质瘤细胞系中的EZH2水平与TMZ的耐药性(以50%抑制率(IC50)表示)呈正相关。此外,与对照细胞相比,EZH2抑制的胶质瘤细胞对TMZ的敏感性更高。此外,我们还发现,在 EZH2 抑制后的 U251 和 U87 脑胶质瘤细胞系中,PARP1 是 DNA 修复蛋白下调的共同分子。有趣的是,EZH2抑制剂还能降低胶质瘤细胞中PARP1的表达。最后,与单独使用EZH2抑制剂和PARP1抑制剂相比,联合使用慢病毒诱导的EZH2抑制剂和PARP1抑制剂能显著增强TMZ的细胞毒性:结论:EZH2-PARP-1 信号轴可能是胶质瘤对 TMZ 产生化疗耐药性的原因。结论:EZH2-PARP-1信号轴可能是胶质瘤对TMZ化疗耐药的原因,同时抑制这两个基因可能会改善TMZ化疗的效果。
{"title":"EZH2-regulated PARP-1 Expression is a Likely Mechanism for the Chemoresistance of Gliomas to Temozolomide.","authors":"Qiang Liang, Bing Wang, Chenran Zhang, Chaoli Song, Junyu Wang, Wei Sun, Lei Jiang, Jing Lin","doi":"10.2174/1568009623666230818151830","DOIUrl":"10.2174/1568009623666230818151830","url":null,"abstract":"<p><strong>Background: </strong>Chemoresistance in gliomas accounts for the major cause of tumor progress and recurrence during comprehensive treatment with alkylating agents including temozolomide (TMZ). The oncogenic role of Enhancer of zeste homolog 2 (EZH2) has been identified in many solid malignancies including gliomas, though the accurate effect of EZH2 on chemotherapy resistance of gliomas has been elusive.</p><p><strong>Objective: </strong>To elucidate the role of EHZ2 on TMZ resistance of gliomas and the molecular mechanisms.</p><p><strong>Methods: </strong>Immunohistochemistry (IHC) and Reverse transcription-quantitative (RT-q) PCR, and western blot assay were performed for expressional analysis. Cell Counting Kit-8 (CCK-8) assay was applied to determine the TMZ sensitivity. EZH2-silencing lentivirus was generated for mechanic study.</p><p><strong>Results: </strong>EZH2 was overexpressed in gliomas both at the transcriptional and protein levels. EZH2 level in glioma cell lines was positively correlated with resistance to TMZ, represented by the 50% inhibition rate (IC<sub>50</sub>). Moreover, there was increased TMZ sensitivity in EZH2-inhibited glioma cells than in the control cells. Furthermore, we determined that PARP1 was a common molecule among the downregulated DNA repair proteins in both U251 and U87 glioma cell lines after EZH2 inhibition. Specifically, we observed a spontaneous increase of PARP1 expression with TMZ treatment and interestingly, the increase of PARP1 could be also reduced by EZH2 inhibition in the glioma cells. Finally, combined treatment with lentivirus-induced EZH2 inhibition and a PARP1 inhibitor dramatically enhanced TMZ cytotoxicity compared with either one alone.</p><p><strong>Conclusion: </strong>EZH2-PARP-1 signaling axis is possibly responsible for the chemoresistance of gliomas to TMZ. Simultaneously inhibiting these two genes may improve the outcome of TMZ chemotherapy.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10078165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.
{"title":"The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors.","authors":"Jiandong Gui, Hangsheng Zhou, Hongyuan Wan, Dongjie Yang, Qing Liu, Lijie Zhu, Yuanyuan Mi","doi":"10.2174/0115680096262439231023110106","DOIUrl":"10.2174/0115680096262439231023110106","url":null,"abstract":"<p><p>Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11092557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92153096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/0115680096265253231022185008
Xianwei Chen, Fan Ye, Hao He, Gong Chen, Zhifu Chen, En Ye, Bingjan He, Yuqi Yang, Jing Zhang
Background: As the only humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) for giant cell tumour of bone (GCTB) therapy, denosumab has limited antitumour effect on neoplastic stromal cells. Nevertheless, its mechanism of action has not yet been clarified. A previous study has revealed that p62 may play an important role in the antitumour activity of denosumab.
Objective: The study aimed to investigate if the mechanism by which denosumab inhibits GCTB neoplastic stromal cells growth is via p62 modulation and other related mechanisms.
Methods: p62 expression before and after denosumab therapy was analysed by RT‒qPCR, western blot, ELISA, and immunohistochemical assays. Two primary neoplastic stromal cells were isolated from fresh GCTB tumour tissue (L cell) and metastatic tissue (M cell). Cell proliferation, migration, apoptosis, and autophagy were investigated in p62 knockdown neoplastic stromal cells transfected by short hairpin RNA lentivirus in vitro. Tumor growth was evaluated in the chick chorioallantoic membrane model in vivo.
Results: p62 expression was found to be downregulated following denosumab therapy. The patients with a decrease in p62 expression had lower recurrence-free survival rates. The proliferation of M cells was not inhibited by denosumab therapy, but it was restored by p62 knockdown. Moreover, p62 knockdown inhibited tumour growth in vivo. Denosumab induced M cell apoptosis and arrested the cell cycle at the G1/G0 transition and these effects were also enhanced by p62 knockdown. Autophagic flux assays revealed p62 modulation to be dependent on autophagy following denosumab incubation.
Conclusion: Denosumab induced neoplastic stromal cells apoptosis via p62 downregulation dependent on autophagy pathway. The combination of p62 and RANKL knockdown might be a better strategy than RANKL knockdown alone for GCTB targeted therapy.
{"title":"Denosumab Induces Neoplastic Stromal Cell Apoptosis <i>Via</i> p62 Downregulation Dependent on Autophagy Pathway in Giant Cell Tumour of Bone.","authors":"Xianwei Chen, Fan Ye, Hao He, Gong Chen, Zhifu Chen, En Ye, Bingjan He, Yuqi Yang, Jing Zhang","doi":"10.2174/0115680096265253231022185008","DOIUrl":"10.2174/0115680096265253231022185008","url":null,"abstract":"<p><strong>Background: </strong>As the only humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) for giant cell tumour of bone (GCTB) therapy, denosumab has limited antitumour effect on neoplastic stromal cells. Nevertheless, its mechanism of action has not yet been clarified. A previous study has revealed that p62 may play an important role in the antitumour activity of denosumab.</p><p><strong>Objective: </strong>The study aimed to investigate if the mechanism by which denosumab inhibits GCTB neoplastic stromal cells growth is via p62 modulation and other related mechanisms.</p><p><strong>Methods: </strong>p62 expression before and after denosumab therapy was analysed by RT‒qPCR, western blot, ELISA, and immunohistochemical assays. Two primary neoplastic stromal cells were isolated from fresh GCTB tumour tissue (L cell) and metastatic tissue (M cell). Cell proliferation, migration, apoptosis, and autophagy were investigated in p62 knockdown neoplastic stromal cells transfected by short hairpin RNA lentivirus <i>in vitro</i>. Tumor growth was evaluated in the chick chorioallantoic membrane model <i>in vivo</i>.</p><p><strong>Results: </strong>p62 expression was found to be downregulated following denosumab therapy. The patients with a decrease in p62 expression had lower recurrence-free survival rates. The proliferation of M cells was not inhibited by denosumab therapy, but it was restored by p62 knockdown. Moreover, p62 knockdown inhibited tumour growth <i>in vivo</i>. Denosumab induced M cell apoptosis and arrested the cell cycle at the G1/G0 transition and these effects were also enhanced by p62 knockdown. Autophagic flux assays revealed p62 modulation to be dependent on autophagy following denosumab incubation.</p><p><strong>Conclusion: </strong>Denosumab induced neoplastic stromal cells apoptosis <i>via</i> p62 downregulation dependent on autophagy pathway. The combination of p62 and RANKL knockdown might be a better strategy than RANKL knockdown alone for GCTB targeted therapy.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92153095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/0115680096267791231115101107
Ye Zhang, Hai-Jiao Yan, Jun Wu
Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.
胆管癌(CCA)是一种以胆管细胞分化为特征的上皮癌,也是一种纤维增生性肿瘤。其特点是间质致密,肿瘤免疫微环境(TME)复杂。TME 包括细胞和非细胞成分。细胞成分包括 CCA 细胞、免疫细胞和以癌症相关成纤维细胞(CAFs)为代表的间质细胞,而非细胞成分则以细胞外基质(ECM)等间质元素为代表。最近的研究表明,TME 在 CCA 的发生、发展和耐药性中起着重要作用。这些与细胞相关的预后标志物以及细胞间的联系可能会成为潜在的治疗靶点,并在未来为 CCA 带来新的治疗方法。本文旨在总结目前对 CCA 免疫微环境的理解,重点关注微环境中的免疫细胞、间充质细胞、ECM、细胞间相互作用和新陈代谢。
{"title":"The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of Cholangiocarcinoma.","authors":"Ye Zhang, Hai-Jiao Yan, Jun Wu","doi":"10.2174/0115680096267791231115101107","DOIUrl":"10.2174/0115680096267791231115101107","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/1568009623666230712095021
Xintong Peng, Jingfan Zheng, Tianzi Liu, Ziwen Zhou, Chen Song, Yan Geng, Zichuan Wang, Yan Huang
Objective: This review describes the comprehensive portrait of tumor microenvironment (TME). Additionally, we provided a panoramic perspective on the transformation and functions of the diverse constituents in TME, and the underlying mechanisms of drug resistance, beginning with the immune cells and metabolic dynamics within TME. Lastly, we summarized the most auspicious potential therapeutic strategies.
Results: TME is a unique realm crafted by malignant cells to withstand the onslaught of endogenous and exogenous therapies. Recent research has revealed many small-molecule immunotherapies exhibiting auspicious outcomes in preclinical investigations. Furthermore, some pro-immune mechanisms have emerged as a potential avenue. With the advent of nanosystems and precision targeting, targeted therapy has now transcended the "comfort zone" erected by cancer cells within TME.
Conclusion: The ceaseless metamorphosis of TME fosters the intransigent resilience and proliferation of tumors. However, existing therapies have yet to surmount the formidable obstacles posed by TME. Therefore, scientists should investigate potential avenues for therapeutic intervention and design innovative pharmacological and clinical technologies.
{"title":"Tumor Microenvironment Heterogeneity, Potential Therapeutic Avenues, and Emerging Therapies.","authors":"Xintong Peng, Jingfan Zheng, Tianzi Liu, Ziwen Zhou, Chen Song, Yan Geng, Zichuan Wang, Yan Huang","doi":"10.2174/1568009623666230712095021","DOIUrl":"10.2174/1568009623666230712095021","url":null,"abstract":"<p><strong>Objective: </strong>This review describes the comprehensive portrait of tumor microenvironment (TME). Additionally, we provided a panoramic perspective on the transformation and functions of the diverse constituents in TME, and the underlying mechanisms of drug resistance, beginning with the immune cells and metabolic dynamics within TME. Lastly, we summarized the most auspicious potential therapeutic strategies.</p><p><strong>Results: </strong>TME is a unique realm crafted by malignant cells to withstand the onslaught of endogenous and exogenous therapies. Recent research has revealed many small-molecule immunotherapies exhibiting auspicious outcomes in preclinical investigations. Furthermore, some pro-immune mechanisms have emerged as a potential avenue. With the advent of nanosystems and precision targeting, targeted therapy has now transcended the \"comfort zone\" erected by cancer cells within TME.</p><p><strong>Conclusion: </strong>The ceaseless metamorphosis of TME fosters the intransigent resilience and proliferation of tumors. However, existing therapies have yet to surmount the formidable obstacles posed by TME. Therefore, scientists should investigate potential avenues for therapeutic intervention and design innovative pharmacological and clinical technologies.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9934097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/1568009623666230803111718
Nidhi Sudhir Dhote, Rajat Dineshbhai Patel, Utkarsha Kuwar, Mukta Agrawal, Amit Alexander, Parag Jain, Ajazuddin
The temperature-triggered in situ gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved in situ gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems.
{"title":"Application of Thermoresponsive Smart Polymers based <i>in situ</i> Gel as a Novel Carrier for Tumor Targeting.","authors":"Nidhi Sudhir Dhote, Rajat Dineshbhai Patel, Utkarsha Kuwar, Mukta Agrawal, Amit Alexander, Parag Jain, Ajazuddin","doi":"10.2174/1568009623666230803111718","DOIUrl":"10.2174/1568009623666230803111718","url":null,"abstract":"<p><p>The temperature-triggered <i>in situ</i> gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved <i>in situ</i> gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10284191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/0115680096272757231211113206
Gerhard Hamilton, Sandra Stickler, Barbara Rath
Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.
{"title":"Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer.","authors":"Gerhard Hamilton, Sandra Stickler, Barbara Rath","doi":"10.2174/0115680096272757231211113206","DOIUrl":"10.2174/0115680096272757231211113206","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly <i>via</i> the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139563827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Cancer is a major cause of death worldwide. Colorectal cancer is the second most common type. Additional treatments like chemotherapy and radiation therapy may be recommended. Developing new techniques is vital due to drug resistance and a lack of targeted therapies.
Objective: In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic Coxsackievirus A21 (CVA21) on a mouse model of CRC were investigated.
Methods: The therapeutic potency of MSCs loaded with oncolytic CVA21 were evaluated in an experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide (NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-β) in the splenocyte supernatant were all used to evaluate the impact of MSCs loaded with CVA21.
Results: The results of this study showed that the treatment of a mouse model of colorectal cancer with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH. Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion of IL-4, IL-10, and TGF-β.
Conclusion: The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing level of nitric oxide.
{"title":"The Effects of Mesenchymal Stem Cells Loaded with Oncolytic <i>Coxsackievirus A21</i> on Mouse Models of Colorectal Cancer.","authors":"Reza Karbalaee, Saber Mehdizadeh, Hadi Esmaeili Gouvarchin Ghaleh, Morteza Izadi, Bahman Jalali Kondori, Ruhollah Dorostkar, Seyed Morteza Hosseini","doi":"10.2174/0115680096273465231201115839","DOIUrl":"10.2174/0115680096273465231201115839","url":null,"abstract":"<p><strong>Background: </strong>Cancer is a major cause of death worldwide. Colorectal cancer is the second most common type. Additional treatments like chemotherapy and radiation therapy may be recommended. Developing new techniques is vital due to drug resistance and a lack of targeted therapies.</p><p><strong>Objective: </strong>In this study, the effects of mesenchymal stem cells (MSCs) loaded with oncolytic <i>Coxsackievirus A21</i> (CVA21) on a mouse model of CRC were investigated.</p><p><strong>Methods: </strong>The therapeutic potency of MSCs loaded with oncolytic CVA21 were evaluated in an experimental mouse model of colorectal cancer which received an injection CT26 cells per mouse subcutaneously. Splenocyte proliferation index, lactate dehydrogenase (LDH) assay, nitric oxide (NO) production assessment, and cytokine assay (IFN-γ, IL-4, IL-10, and TGF-β) in the splenocyte supernatant were all used to evaluate the impact of MSCs loaded with CVA21.</p><p><strong>Results: </strong>The results of this study showed that the treatment of a mouse model of colorectal cancer with MSCs loaded with oncolytic CVA21 could significantly suppress the tumor growth, which was accompanied by stimulation of splenocytes proliferation index, an increase of NO and LDH. Also, MSCs loaded with oncolytic CVA21 increased the secretion of IFN-γ and decreased the secretion of IL-4, IL-10, and TGF-β.</p><p><strong>Conclusion: </strong>The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing level of nitric oxide.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/0115680096276852231113111412
Ting-Yu Fan, Li-Li Xu, Hong-Feng Zhang, Juan Peng, Dan Liu, Wen-Da Zou, Wen-Jie Feng, Mei Qin, Juan Zhang, Hui Li, Yu-Kun Li
Background: Ovarian cancer (OC) is one of the malignant diseases of the reproductive system in elderly women. Aging-related genes (ARGs) were involved in tumor malignancy and cellular senescence, but the specifics of these mechanisms in OC remain unknown.
Methods: ARGs expression and survival data of OC patients were collected from TCGA and CPTAC databases. Subtype classification was used to identify the roles of hub ARGs in OC progression, including function enrichment, immune infiltration, and drug sensitivity. LASSO regression was utilized to confirm the prognosis significance for these hub ARGs. MTT, EdU, Transwell, and wounding healing analysis confirmed the effect of IGFBP5 on the proliferation and migration ability of OC cells.
Results: ARGs were ectopically expressed in OC tissues compared to normal ovary tissues. Three molecular subtypes were divided by ARGs for OC patients. There were significant differences in ferroptosis, m6A methylation, prognosis, immune infiltration, angiogenesis, differentiation level, and drug sensitivity among the three groups. LASSO regression indicated that 4 signatures, FOXO4, IGFBP5, OGG1 and TYMS, had important prognosis significance. Moreover, IGFBP5 was significantly correlated with immune infiltration. The hub ARG, IGFBP5, expression was significantly decreased in OC patients compared to normal women. IGFBP5 could also reduce the migration and proliferation ability of OC cells compared to vector and NC groups.
Conclusion: IGFBP5 was correlated with OC prognosis and associated with OC migration and proliferation. This gene may serve as potential prognostic biomarkers and therapeutic targets for OC patients.
{"title":"Comprehensive Analyses and Experiments Confirmed IGFBP5 as a Prognostic Predictor Based on an Aging-genomic Landscape Analysis of Ovarian Cancer.","authors":"Ting-Yu Fan, Li-Li Xu, Hong-Feng Zhang, Juan Peng, Dan Liu, Wen-Da Zou, Wen-Jie Feng, Mei Qin, Juan Zhang, Hui Li, Yu-Kun Li","doi":"10.2174/0115680096276852231113111412","DOIUrl":"10.2174/0115680096276852231113111412","url":null,"abstract":"<p><strong>Background: </strong>Ovarian cancer (OC) is one of the malignant diseases of the reproductive system in elderly women. Aging-related genes (ARGs) were involved in tumor malignancy and cellular senescence, but the specifics of these mechanisms in OC remain unknown.</p><p><strong>Methods: </strong>ARGs expression and survival data of OC patients were collected from TCGA and CPTAC databases. Subtype classification was used to identify the roles of hub ARGs in OC progression, including function enrichment, immune infiltration, and drug sensitivity. LASSO regression was utilized to confirm the prognosis significance for these hub ARGs. MTT, EdU, Transwell, and wounding healing analysis confirmed the effect of IGFBP5 on the proliferation and migration ability of OC cells.</p><p><strong>Results: </strong>ARGs were ectopically expressed in OC tissues compared to normal ovary tissues. Three molecular subtypes were divided by ARGs for OC patients. There were significant differences in ferroptosis, m6A methylation, prognosis, immune infiltration, angiogenesis, differentiation level, and drug sensitivity among the three groups. LASSO regression indicated that 4 signatures, FOXO4, IGFBP5, OGG1 and TYMS, had important prognosis significance. Moreover, IGFBP5 was significantly correlated with immune infiltration. The hub ARG, IGFBP5, expression was significantly decreased in OC patients compared to normal women. IGFBP5 could also reduce the migration and proliferation ability of OC cells compared to vector and NC groups.</p><p><strong>Conclusion: </strong>IGFBP5 was correlated with OC prognosis and associated with OC migration and proliferation. This gene may serve as potential prognostic biomarkers and therapeutic targets for OC patients.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138451142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.2174/0115680096282480240105071638
Vladimir Rogovskii
Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.
{"title":"Cancer and Autoimmune Diseases as Two Sides of Chronic Inflammation and the Method of Therapy.","authors":"Vladimir Rogovskii","doi":"10.2174/0115680096282480240105071638","DOIUrl":"10.2174/0115680096282480240105071638","url":null,"abstract":"<p><p>Chronic inflammation is associated with a prolonged increase in various inflammatory factors. According to clinical data, it can be linked with both cancer and autoimmune diseases in the same patients. This raises the critical question of how chronic inflammation relates to seemingly opposing diseases - tumors, in which there is immunosuppression, and autoimmune diseases, in which there is over-activation of the immune system. In this review, we consider chronic inflammation as a prerequisite for both immune suppression and an increased likelihood of autoimmune damage. We also discuss potential disease-modifying therapies targeting chronic inflammation, which can be helpful for both cancer and autoimmunity. On the one hand, pro-inflammatory factors persisting in the areas of chronic inflammation stimulate the production of anti-inflammatory factors due to a negative feedback loop, eliciting immune suppression. On the other hand, chronic inflammation can bring the baseline immunity closer to the threshold level required for triggering an autoimmune response using the bystander activation of immune cells. Focusing on the role of chronic inflammation in cancer and autoimmune diseases may open prospects for more intensive drug discovery for chronic inflammation.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}