Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.
{"title":"Decitabine suppresses MDSC-induced immunosuppression through dual functional mechanism and inhibits melanoma metastasis.","authors":"Zhonghai Zhang, Tianlong Wang, Gaochuan Fang, Xufeng Xiao, Zhengkui Zhang, Jiaojiao Zhao","doi":"10.1007/s12032-024-02320-w","DOIUrl":"10.1007/s12032-024-02320-w","url":null,"abstract":"<p><p>Myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting melanoma metastasis. Reprogramming MDSCs into mature M1 macrophages has emerged as a strategy to inhibit metastasis. Decitabine (Dec) is known to eradicate MDSCs and suppress tumor growth. In this study, we provide evidence that Dec not only reduces the MDSC population by inducing apoptosis, arresting cell cycle, and impairing recruitment, but also suppresses their immunosuppressive function by downregulating related genes and facilitating differentiation into M1 macrophages. Transcriptomic analysis of Dec-treated MDSCs revealed a marked downregulation of immunosuppressive genes including S100a9, S100a8, Vegf, Cxcr2, and Nos2. Meanwhile, M1 macrophage-associated genes involved in immune activation were upregulated, such as Ddx58, Isg15, Tap1, Ccl5, Cxcl9, and Cxcl10. Further bioinformatic analysis indicated that Dec promotes MDSC-to-M1 macrophage differentiation and activates innate immune pathways including NOD-like signaling to enhance anti-tumor immunity. Time-course studies implied that Dec upregulates myeloid transcription factor Irf7 to initiate MDSC differentiation and orchestrate the anti-tumor immune response. Collectively, our study unveils a novel dual-functional mechanism of Dec as both a cytotoxic agent reducing MDSCs and an inducer of their differentiation into M1 macrophages, thereby alleviating immunosuppression. This highlights Dec's potential for clinical melanoma metastasis suppression.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179853","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 : 2024-05-30DOI: 10.1007/s12032-024-02387-5
Lunasmrita Saikia, Bhaskarjyoti Gogoi, Saikat Sen, Rajiv K Tonk, Deepak Kumar, Partha Pratim Dutta
The Wnt/β-Catenin pathway (Wnt/β-CatP) is implicated in accelerating carcinogenesis and cancer progression, contributing to increased morbidity and treatment resistance. Even though it holds promise as a focus for cancer treatment, its intricate nature and diverse physiological effects pose significant challenges. Recent years have witnessed significant advancements in this domain, with numerous natural products demonstrating promising preclinical anti-tumor effects and identified as inhibitors of the Wnt/β-CatP through various upstream and downstream mechanisms. This study provides a comprehensive overview of the current landscape of Wnt/β-Cat-targeted cancer therapy, examining the impact of natural products on Wnt/β-Cat signaling in both cancer prevention and therapeutic contexts. A comprehensive search was conducted on scientific databases like SciFinder, PubMed, and Google Scholar to retrieve relevant literature on Wnt-signaling, natural products, β-Catenin (β-Cat), and cancer from 2020 to January 2024. As per the analysis of the relevant reference within the specified period, it has been noted that a total of 58 phytoconstituents, predominantly phenolics, followed by triterpenoids and several other classes, along with a limited number of plant extracts, have exhibited activity targeting the Wnt/β-CatP. Most β-Cat regulating modulators restrict cancer cell development by suppressing β-Cat expression, facilitating proteasomal degradation, and inhibiting nuclear translocation. Multiple approaches have been devised to block the activity of β-Cat in cancer therapy, a key factor in cancer progression, leading to the discovery of various Wnt/β-CatP regulators. However, their exploration remains limited, necessitating further research using clinical models for potential clinical use in cancer prevention and therapeutics.
{"title":"The recent update and advancements of natural products in targeting the Wnt/β-Catenin pathway for cancer prevention and therapeutics.","authors":"Lunasmrita Saikia, Bhaskarjyoti Gogoi, Saikat Sen, Rajiv K Tonk, Deepak Kumar, Partha Pratim Dutta","doi":"10.1007/s12032-024-02387-5","DOIUrl":"10.1007/s12032-024-02387-5","url":null,"abstract":"<p><p>The Wnt/β-Catenin pathway (Wnt/β-CatP) is implicated in accelerating carcinogenesis and cancer progression, contributing to increased morbidity and treatment resistance. Even though it holds promise as a focus for cancer treatment, its intricate nature and diverse physiological effects pose significant challenges. Recent years have witnessed significant advancements in this domain, with numerous natural products demonstrating promising preclinical anti-tumor effects and identified as inhibitors of the Wnt/β-CatP through various upstream and downstream mechanisms. This study provides a comprehensive overview of the current landscape of Wnt/β-Cat-targeted cancer therapy, examining the impact of natural products on Wnt/β-Cat signaling in both cancer prevention and therapeutic contexts. A comprehensive search was conducted on scientific databases like SciFinder, PubMed, and Google Scholar to retrieve relevant literature on Wnt-signaling, natural products, β-Catenin (β-Cat), and cancer from 2020 to January 2024. As per the analysis of the relevant reference within the specified period, it has been noted that a total of 58 phytoconstituents, predominantly phenolics, followed by triterpenoids and several other classes, along with a limited number of plant extracts, have exhibited activity targeting the Wnt/β-CatP. Most β-Cat regulating modulators restrict cancer cell development by suppressing β-Cat expression, facilitating proteasomal degradation, and inhibiting nuclear translocation. Multiple approaches have been devised to block the activity of β-Cat in cancer therapy, a key factor in cancer progression, leading to the discovery of various Wnt/β-CatP regulators. However, their exploration remains limited, necessitating further research using clinical models for potential clinical use in cancer prevention and therapeutics.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179872","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 : 2024-05-23DOI: 10.1007/s12032-024-02358-w
Yan-Ling Wu, Wan Liu, Tingting Zhao, Jing Jin
Head and neck squamous cell carcinoma (HNSCC) can be defined as a deadly illness with a dismal prognosis in advanced stages. Therefore, we seek to examine P4HA2 expression and effect in HNSCC, along with the underlying mechanisms. This study utilized integrated bioinformatics analyses to evaluate the P4HA2 expression pattern, prognostic implication, and probable function in HNSCC. The study conducted various in vitro experiments, including colony formation, CCK-8, flow cytometry, wound healing, and transwell assays, on the human HNSCC cell line CAL-27 to examine the involvement of P4HA2 in HNSCC progression. Moreover, western blotting was used to investigate epithelial-mesenchymal transition (EMT) markers and PI3K/AKT pathway markers to elucidate the underlying mechanisms. P4HA2 expression was significantly enhanced in HNSCC, and its overexpression was correlated to tumor aggressiveness and a poor prognosis in patients. Based on in vitro experiments, the overexpressed P4HA2 enhanced cell proliferation, migration, invasion, as well as EMT while reducing apoptosis, whereas P4HA2 silencing exhibited the reverse effect. P4HA2 overexpression enhanced PI3K/AKT phosphorylation in HNSCC cells. Moreover, LY294002 was observed to counteract the effects of upregulated P4HA2 on proliferation, migration, invasion, and EMT in HNSCC. Collectively, we indicated that P4HA2 promoted HNSCC progression and EMT via PI3K/AKT signaling pathway.
{"title":"P4HA2 contributes to head and neck squamous cell carcinoma progression and EMT through PI3K/AKT signaling pathway.","authors":"Yan-Ling Wu, Wan Liu, Tingting Zhao, Jing Jin","doi":"10.1007/s12032-024-02358-w","DOIUrl":"10.1007/s12032-024-02358-w","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) can be defined as a deadly illness with a dismal prognosis in advanced stages. Therefore, we seek to examine P4HA2 expression and effect in HNSCC, along with the underlying mechanisms. This study utilized integrated bioinformatics analyses to evaluate the P4HA2 expression pattern, prognostic implication, and probable function in HNSCC. The study conducted various in vitro experiments, including colony formation, CCK-8, flow cytometry, wound healing, and transwell assays, on the human HNSCC cell line CAL-27 to examine the involvement of P4HA2 in HNSCC progression. Moreover, western blotting was used to investigate epithelial-mesenchymal transition (EMT) markers and PI3K/AKT pathway markers to elucidate the underlying mechanisms. P4HA2 expression was significantly enhanced in HNSCC, and its overexpression was correlated to tumor aggressiveness and a poor prognosis in patients. Based on in vitro experiments, the overexpressed P4HA2 enhanced cell proliferation, migration, invasion, as well as EMT while reducing apoptosis, whereas P4HA2 silencing exhibited the reverse effect. P4HA2 overexpression enhanced PI3K/AKT phosphorylation in HNSCC cells. Moreover, LY294002 was observed to counteract the effects of upregulated P4HA2 on proliferation, migration, invasion, and EMT in HNSCC. Collectively, we indicated that P4HA2 promoted HNSCC progression and EMT via PI3K/AKT signaling pathway.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080761","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}
Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality due to the emergence of drug resistance to anticancer drugs. These resistance events have a very well-understood underlying mechanism, and their therapeutic relevance has long been recognized. Thus, drug resistance continues to be a major obstacle to providing cancer patients with the intended "cure". PAQR4 (Progestin and AdipoQ Receptor Family Member 4) gene is a recently identified novel protein-coding gene associated with various human cancers and acts through different signaling pathways. PAQR4 has a significant influence on multiple proteins that may regulate various gene expressions and may develop chemoresistance. This review discusses the roles of PAQR4 in tumor immunity, carcinogenesis, and chemoresistance. This paper is the first review, discussing PAQR4 in the pathogenesis of cancer. The review further explores the PAQR4 as a potential target in various malignancies.
尽管进行了数十年的基础和临床研究,并对前景看好的新疗法进行了试验,但由于抗癌药物耐药性的出现,癌症仍然是发病和死亡的主要原因。这些耐药事件的基本机制已被很好地理解,其治疗相关性也早已得到认可。因此,耐药性仍然是癌症患者获得预期 "治愈 "的主要障碍。PAQR4(Progestin and AdipoQ Receptor Family Member 4,孕激素和脂肪Q受体家族成员4)基因是最近发现的一种与多种人类癌症相关的新型蛋白编码基因,它通过不同的信号通路发挥作用。PAQR4 对多种蛋白质有重大影响,这些蛋白质可能会调控各种基因表达,并可能产生化疗抗药性。本综述讨论 PAQR4 在肿瘤免疫、癌变和化疗抗性中的作用。本文是第一篇讨论 PAQR4 在癌症发病机制中作用的综述。该综述进一步探讨了 PAQR4 在各种恶性肿瘤中作为潜在靶点的作用。
{"title":"PAQR4 oncogene: a novel target for cancer therapy.","authors":"Dipti Patil, Swapnil Raut, Mitesh Joshi, Purvi Bhatt, Lokesh Kumar Bhatt","doi":"10.1007/s12032-024-02382-w","DOIUrl":"10.1007/s12032-024-02382-w","url":null,"abstract":"<p><p>Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality due to the emergence of drug resistance to anticancer drugs. These resistance events have a very well-understood underlying mechanism, and their therapeutic relevance has long been recognized. Thus, drug resistance continues to be a major obstacle to providing cancer patients with the intended \"cure\". PAQR4 (Progestin and AdipoQ Receptor Family Member 4) gene is a recently identified novel protein-coding gene associated with various human cancers and acts through different signaling pathways. PAQR4 has a significant influence on multiple proteins that may regulate various gene expressions and may develop chemoresistance. This review discusses the roles of PAQR4 in tumor immunity, carcinogenesis, and chemoresistance. This paper is the first review, discussing PAQR4 in the pathogenesis of cancer. The review further explores the PAQR4 as a potential target in various malignancies.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065908","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 : 2024-05-20DOI: 10.1007/s12032-024-02380-y
Ruqian Zhang, Yongbo Yu, Yeran Yang, Meng Zhang, Xuan Zhang, Yan Chang, Shengcai Wang, Linfei Hu, Jiali Li, Xiangqian Zheng, Ruili Zhao, Yongli Guo, Xin Ni
Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.
{"title":"Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression.","authors":"Ruqian Zhang, Yongbo Yu, Yeran Yang, Meng Zhang, Xuan Zhang, Yan Chang, Shengcai Wang, Linfei Hu, Jiali Li, Xiangqian Zheng, Ruili Zhao, Yongli Guo, Xin Ni","doi":"10.1007/s12032-024-02380-y","DOIUrl":"10.1007/s12032-024-02380-y","url":null,"abstract":"<p><p>Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065911","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 : 2024-05-20DOI: 10.1007/s12032-024-02384-8
Fatemeh Khak-Rah Nasirabadi, Abbas Doosti
Dermaseptin B2 (DrsB2) is an antimicrobial peptide with anticancer and angiostatic properties. We aimed to assess the in vitro inhibitory effect of pDNA/DrsB2 on the growth of breast cancer cells and its impact on the expression of genes involved in the BAX/BBC3/AKT pathway. The nucleic acid sequence of DrsB2 was artificially synthesized and inserted into the pcDNA3.1( +) Mammalian Expression Plasmid. PCR testing and enzyme digesting procedures evaluated the accuracy of cloning. The vectors were introduced into cells using LipofectamineTM2000 transfection reagent. The breast cancer cells were assessed by flow cytometry, MTT assessment, soft agar colony method, and wound healing investigation. The gene's transcription was evaluated using real-time PCR with a significance level of P < 0.05. The recombinant plasmid harboring the pDNA/DrsB2 vector was effectively produced, and the gene sequence showed absolute homogeneity (100% similarity) with the DrsB2 gene. The transfection effectiveness of MCF-7 and MCF-10A cells was 79% and 68%, respectively. The findings are measured using the growth inhibition 50% (GI50) metric, which indicates the concentration of pDNA/DrsB2 that stops 50% of cell growth. The proportions of early apoptosis, late apoptosis, necrosis, and viable MCF-7 cells in the pDNA/DrsB2 group were 40.50%, 2.31%, 1.69%, and 55.50%, respectively. The results showed a 100% increase in gene expression in programmed cell death following treatment with pDNA/DrsB2 (**P < 0.01). To summarize, the results described in this work offer new possibilities for treating cancer by targeting malignancies via pDNA/DrsB2 and activating the BAX/BBC3/AKT signaling pathways.
{"title":"Dermaseptin B2 bioactive gene's potential for anticancer and anti-proliferative effect is linked to the regulation of the BAX/BBC3/AKT pathway.","authors":"Fatemeh Khak-Rah Nasirabadi, Abbas Doosti","doi":"10.1007/s12032-024-02384-8","DOIUrl":"10.1007/s12032-024-02384-8","url":null,"abstract":"<p><p>Dermaseptin B2 (DrsB2) is an antimicrobial peptide with anticancer and angiostatic properties. We aimed to assess the in vitro inhibitory effect of pDNA/DrsB2 on the growth of breast cancer cells and its impact on the expression of genes involved in the BAX/BBC3/AKT pathway. The nucleic acid sequence of DrsB2 was artificially synthesized and inserted into the pcDNA3.1( +) Mammalian Expression Plasmid. PCR testing and enzyme digesting procedures evaluated the accuracy of cloning. The vectors were introduced into cells using LipofectamineTM2000 transfection reagent. The breast cancer cells were assessed by flow cytometry, MTT assessment, soft agar colony method, and wound healing investigation. The gene's transcription was evaluated using real-time PCR with a significance level of P < 0.05. The recombinant plasmid harboring the pDNA/DrsB2 vector was effectively produced, and the gene sequence showed absolute homogeneity (100% similarity) with the DrsB2 gene. The transfection effectiveness of MCF-7 and MCF-10A cells was 79% and 68%, respectively. The findings are measured using the growth inhibition 50% (GI50) metric, which indicates the concentration of pDNA/DrsB2 that stops 50% of cell growth. The proportions of early apoptosis, late apoptosis, necrosis, and viable MCF-7 cells in the pDNA/DrsB2 group were 40.50%, 2.31%, 1.69%, and 55.50%, respectively. The results showed a 100% increase in gene expression in programmed cell death following treatment with pDNA/DrsB2 (**P < 0.01). To summarize, the results described in this work offer new possibilities for treating cancer by targeting malignancies via pDNA/DrsB2 and activating the BAX/BBC3/AKT signaling pathways.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065940","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 : 2024-05-18DOI: 10.1007/s12032-024-02402-9
Chunyu Wu, Lvyuan Li, Qiling Tang, Qianjin Liao, Pan Chen, Can Guo, Zhaoyang Zeng, Wei Xiong
RNA modification has garnered increasing attention in recent years due to its pivotal role in tumorigenesis and immune surveillance. N6-methyladenosine (m6A) modification is the most prevalent RNA modification, which can affect the expression of RNA by methylating adenylate at the sixth N position to regulate the occurrence and development of tumors. Dysregulation of m6A affects the activation of cancer-promoting pathways, destroys immune cell function, maintains immunosuppressive microenvironment, and promotes tumor cell growth. In this review, we delve into the latest insights into how abnormalities in m6A modification in both tumor and immune cells orchestrate immune evasion through the activation of signaling pathways. Furthermore, we explore how dysregulated m6A modification in tumor cells influences immune cells, thereby regulating tumor immune evasion via interactions within the tumor microenvironment (TME). Lastly, we highlight recent discoveries regarding specific inhibitors of m6A modulators and the encapsulation of m6A-targeting nanomaterials for cancer therapy, discussing their potential applications in immunotherapy.
{"title":"Role of m<sup>6</sup>A modifications in immune evasion and immunotherapy.","authors":"Chunyu Wu, Lvyuan Li, Qiling Tang, Qianjin Liao, Pan Chen, Can Guo, Zhaoyang Zeng, Wei Xiong","doi":"10.1007/s12032-024-02402-9","DOIUrl":"10.1007/s12032-024-02402-9","url":null,"abstract":"<p><p>RNA modification has garnered increasing attention in recent years due to its pivotal role in tumorigenesis and immune surveillance. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification is the most prevalent RNA modification, which can affect the expression of RNA by methylating adenylate at the sixth N position to regulate the occurrence and development of tumors. Dysregulation of m<sup>6</sup>A affects the activation of cancer-promoting pathways, destroys immune cell function, maintains immunosuppressive microenvironment, and promotes tumor cell growth. In this review, we delve into the latest insights into how abnormalities in m<sup>6</sup>A modification in both tumor and immune cells orchestrate immune evasion through the activation of signaling pathways. Furthermore, we explore how dysregulated m<sup>6</sup>A modification in tumor cells influences immune cells, thereby regulating tumor immune evasion via interactions within the tumor microenvironment (TME). Lastly, we highlight recent discoveries regarding specific inhibitors of m<sup>6</sup>A modulators and the encapsulation of m<sup>6</sup>A-targeting nanomaterials for cancer therapy, discussing their potential applications in immunotherapy.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956690","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 : 2024-05-18DOI: 10.1007/s12032-024-02379-5
Shabnum Shaheen, Sana Khalid, Khadija Aaliya, Ambreen Gul, Amna Hafeez, Muhammad Armaghan, Zainab M Almarhoon, Daniela Calina, Khushbukhat Khan, Javad Sharifi-Rad
Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential.
{"title":"Insights into Nimbolide molecular crosstalk and its anticancer properties.","authors":"Shabnum Shaheen, Sana Khalid, Khadija Aaliya, Ambreen Gul, Amna Hafeez, Muhammad Armaghan, Zainab M Almarhoon, Daniela Calina, Khushbukhat Khan, Javad Sharifi-Rad","doi":"10.1007/s12032-024-02379-5","DOIUrl":"10.1007/s12032-024-02379-5","url":null,"abstract":"<p><p>Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956549","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 : 2024-05-17DOI: 10.1007/s12032-024-02385-7
Lindsay Holic
It has long been recognized that a history of skin cancer puts one at risk for additional primary skin cancers. However, more variable data exists for the risk of developing a non-cutaneous primary cancer following a diagnosis of skin cancer. The data are most variable for Basal Cell Carcinoma (BCC), the most common and least aggressive type of skin cancer. While early studies imply that BCC does not impart a larger risk of other primary non-cutaneous cancers, more recent studies with larger populations suggest otherwise. The cancers most significantly associated with BCC are lip, oropharyngeal, and salivary gland cancer. There is also burgeoning evidence to suggest a link between BCC and prostate, breast, and colorectal cancer, but more data are needed to draw a concrete conclusion. Squamous Cell Carcinoma (SCC), the second most common type of skin cancer, has a slightly more defined risk to other non-cutaneous primary malignancies. There is a notable link between SCC and non-Hodgkin's lymphoma (NHL), possibly due to immunosuppression. There is also an increased risk of other cancers derived from squamous epithelium following SCC, including oropharyngeal, lip, and salivary gland cancer. Some studies also suggest an increased risk of respiratory tract cancer following SCC, possibly due to shared risk factors. Melanoma, a more severe type of skin cancer, shows a well-defined risk of additional primary non-cutaneous malignancies. The most significant of these risks include NHL, thyroid cancer, prostate cancer, and breast cancer along with a host of other cancers. Each of these three main skin cancer types has a profile of genetic mutations that have also been linked to non-cutaneous malignancies. In this review, we discuss a selection of these genes to highlight the complex interplay between different tumorigenesis processes.
{"title":"Common skin cancers and their association with other non-cutaneous primary malignancies: a review of the literature.","authors":"Lindsay Holic","doi":"10.1007/s12032-024-02385-7","DOIUrl":"10.1007/s12032-024-02385-7","url":null,"abstract":"<p><p>It has long been recognized that a history of skin cancer puts one at risk for additional primary skin cancers. However, more variable data exists for the risk of developing a non-cutaneous primary cancer following a diagnosis of skin cancer. The data are most variable for Basal Cell Carcinoma (BCC), the most common and least aggressive type of skin cancer. While early studies imply that BCC does not impart a larger risk of other primary non-cutaneous cancers, more recent studies with larger populations suggest otherwise. The cancers most significantly associated with BCC are lip, oropharyngeal, and salivary gland cancer. There is also burgeoning evidence to suggest a link between BCC and prostate, breast, and colorectal cancer, but more data are needed to draw a concrete conclusion. Squamous Cell Carcinoma (SCC), the second most common type of skin cancer, has a slightly more defined risk to other non-cutaneous primary malignancies. There is a notable link between SCC and non-Hodgkin's lymphoma (NHL), possibly due to immunosuppression. There is also an increased risk of other cancers derived from squamous epithelium following SCC, including oropharyngeal, lip, and salivary gland cancer. Some studies also suggest an increased risk of respiratory tract cancer following SCC, possibly due to shared risk factors. Melanoma, a more severe type of skin cancer, shows a well-defined risk of additional primary non-cutaneous malignancies. The most significant of these risks include NHL, thyroid cancer, prostate cancer, and breast cancer along with a host of other cancers. Each of these three main skin cancer types has a profile of genetic mutations that have also been linked to non-cutaneous malignancies. In this review, we discuss a selection of these genes to highlight the complex interplay between different tumorigenesis processes.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958449","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 : 2024-05-15DOI: 10.1007/s12032-024-02406-5
B Stany, Shatakshi Mishra, K V Bhaskara Rao
This study explores the therapeutic potential of phytochemicals derived from Morus alba for colorectal cancer (CRC) treatment. Colorectal cancer is a global health concern with increasing mortality rates, necessitating innovative strategies for prevention and therapy. Employing in silico analysis, molecular docking techniques (MDT), and molecular dynamics simulations (MDS), the study investigates the interactions between Morus alba-derived phytochemicals and key proteins (AKT1, Src, STAT3, EGFR) implicated in CRC progression. ADME/T analysis screens 78 phytochemicals for drug-like and pharmacokinetic properties. The study integrates Lipinski's Rule of Five and comprehensive bioactivity assessments, providing a nuanced understanding of Morus alba phytoconstituent's potential as CRC therapeutic agents. Notably, 14 phytochemicals out of 78 emerge as potential candidates, demonstrating oral bioavailability and favorable bioactivity scores. Autodock 1.5.7 is employed for energy minimization followed by molecular docking with the highest binding energy observed to be - 11.7 kcal/mol exhibited by Kuwanon A against AKT1. Molecular dynamics simulations and trajectory path analysis were conducted between Kuwanon A and AKT1 at the Pleckstrin homology (PH) domain region (TRP80), revealing minimal deviations. In comparison to the standard drug Capivasertib, the phytochemical Kuwanon A emerges as a standout candidate based on computational analysis. This suggests its potential as an alternative to mitigate the limitations associated with the standard drug. The research aims to provide insights for future experimental validations and to stimulate the development of Kuwanon A as a novel, effective therapeutic agent for managing colorectal cancer.
本研究探讨了从桑白皮中提取的植物化学物质在治疗结直肠癌(CRC)方面的潜力。结直肠癌是一个全球关注的健康问题,死亡率不断上升,因此需要创新的预防和治疗策略。该研究采用硅学分析、分子对接技术(MDT)和分子动力学模拟(MDS),研究了桑白皮提取的植物化学物质与牵涉到 CRC 进展的关键蛋白(AKT1、Src、STAT3、EGFR)之间的相互作用。ADME/T 分析筛选了 78 种植物化学物质的类药物和药代动力学特性。该研究整合了利宾斯基的 "五法则 "和全面的生物活性评估,提供了对桑白皮植物成分作为 CRC 治疗药物潜力的细致理解。值得注意的是,在 78 种植物化学物质中,有 14 种显示出口服生物利用度和良好的生物活性。采用 Autodock 1.5.7 进行能量最小化,然后进行分子对接,观察到 Kuwanon A 与 AKT1 的最高结合能为 - 11.7 kcal/mol。对 Kuwanon A 和 AKT1 在 Pleckstrin 同源(PH)结构域区域(TRP80)进行了分子动力学模拟和轨迹路径分析,结果显示偏差极小。根据计算分析,与标准药物 Capivasertib 相比,植物化学物质 Kuwanon A 是一个突出的候选药物。这表明它有潜力成为一种替代药物,以缓解标准药物的相关局限性。这项研究旨在为未来的实验验证提供见解,并促进 Kuwanon A 作为一种新型、有效的结直肠癌治疗药物的开发。
{"title":"Pharmacokinetic studies, molecular docking, and molecular dynamics simulations of phytochemicals from Morus alba: a multi receptor approach for potential therapeutic agents in colorectal cancer.","authors":"B Stany, Shatakshi Mishra, K V Bhaskara Rao","doi":"10.1007/s12032-024-02406-5","DOIUrl":"10.1007/s12032-024-02406-5","url":null,"abstract":"<p><p>This study explores the therapeutic potential of phytochemicals derived from Morus alba for colorectal cancer (CRC) treatment. Colorectal cancer is a global health concern with increasing mortality rates, necessitating innovative strategies for prevention and therapy. Employing in silico analysis, molecular docking techniques (MDT), and molecular dynamics simulations (MDS), the study investigates the interactions between Morus alba-derived phytochemicals and key proteins (AKT1, Src, STAT3, EGFR) implicated in CRC progression. ADME/T analysis screens 78 phytochemicals for drug-like and pharmacokinetic properties. The study integrates Lipinski's Rule of Five and comprehensive bioactivity assessments, providing a nuanced understanding of Morus alba phytoconstituent's potential as CRC therapeutic agents. Notably, 14 phytochemicals out of 78 emerge as potential candidates, demonstrating oral bioavailability and favorable bioactivity scores. Autodock 1.5.7 is employed for energy minimization followed by molecular docking with the highest binding energy observed to be - 11.7 kcal/mol exhibited by Kuwanon A against AKT1. Molecular dynamics simulations and trajectory path analysis were conducted between Kuwanon A and AKT1 at the Pleckstrin homology (PH) domain region (TRP80), revealing minimal deviations. In comparison to the standard drug Capivasertib, the phytochemical Kuwanon A emerges as a standout candidate based on computational analysis. This suggests its potential as an alternative to mitigate the limitations associated with the standard drug. The research aims to provide insights for future experimental validations and to stimulate the development of Kuwanon A as a novel, effective therapeutic agent for managing colorectal cancer.</p>","PeriodicalId":18433,"journal":{"name":"Medical Oncology","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140945404","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}