Cellular Oncology最新文献

{"title":"Identifying cancer subtypes based on embryonic and hematopoietic stem cell signatures in pan-cancer.","authors":"Jiali Lei, Jiangti Luo, Qian Liu, Xiaosheng Wang","doi":"10.1007/s13402-023-00886-7","DOIUrl":"10.1007/s13402-023-00886-7","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer cells with stem cell-like properties may contribute to cancer development and therapy resistance. The advancement of multi-omics technology has sparked interest in exploring cancer stemness from a multi-omics perspective. However, there is a limited number of studies that have attempted to subtype cancer by combining different types of stem cell signatures.</p><p><strong>Methods: </strong>In this study, 10,323 cancer specimens from 33 TCGA cancer types were clustered based on the enrichment scores of six stemness gene sets, representing two types of stem cell backgrounds: embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs).</p><p><strong>Results: </strong>We identified four subtypes of pan-cancer, termed StC1, StC2, StC3 and StC4, which displayed distinct molecular and clinical features, including stemness, genome integrity, intratumor heterogeneity, methylation levels, tumor microenvironment, tumor progression, responses to chemotherapy and immunotherapy, and survival prognosis. Importantly, this subtyping method for pan-cancer is reproducible at the protein level.</p><p><strong>Conclusion: </strong>Our findings indicate that the ESC signature is an adverse prognostic factor in cancer, while the HSC signature and ratio of HSC/ESC signatures are positive prognostic factors. The subtyping of cancer based on ESC and HSC signatures may provide insights into cancer biology and clinical implications of cancer.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"587-605"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41217643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying the effectiveness of 3D culture systems to recapitulate breast tumor tissue in situ.","authors":"Katarzyna A Ludwik, Frances R Greathouse, Samuel Han, Kimberly Stauffer, David R Brenin, Thomas P Stricker, Deborah A Lannigan","doi":"10.1007/s13402-023-00877-8","DOIUrl":"10.1007/s13402-023-00877-8","url":null,"abstract":"<p><strong>Purpose: </strong>Breast cancer heterogeneity contributes to chemotherapy resistance and decreased patient survival. To improve patient outcomes it is essential to develop a technology that is able to rapidly select the most efficacious therapy that targets the diverse phenotypes present within the tumor. Breast cancer organoid technologies are proposed as an attractive approach for evaluating drug responses prior to patient therapy. However, there remain challenges in evaluating the effectiveness of organoid cultures to recapitulate the heterogeneity present in the patient tumor in situ.</p><p><strong>Method: </strong>Organoids were generated from seven normal breast and nineteen breast cancer tissues diagnosed as estrogen receptor positive or triple negative. The Jensen-Shannon divergence index, a measure of the similarity between distributions, was used to compare and evaluate heterogeneity in starting tissue and their resultant organoids. Heterogeneity was analyzed using cytokeratin 8 and cytokeratin 14, which provided an easily scored readout.</p><p><strong>Results: </strong>In the in vitro culture system HER1 and FGFR were able to drive intra-tumor heterogeneity to generate divergent phenotypes that have different sensitivities to chemotherapies.</p><p><strong>Conclusion: </strong>Our methodology, which focuses on quantifiable cellular phenotypes, provides a tractable system that complements omics approaches to provide an unprecedented view of heterogeneity and will enhance the identification of novel therapies and facilitate personalized medicine.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"481-496"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune characteristics associated with lymph node metastasis in early-stage NSCLC.","authors":"Ziyu Zhang, Li Li, Yang Gao, Xiaoxiong Xiao, Liyan Ji, Zhipeng Zhou, Juan Jiang, Shiqing Liu, Jian An, Pengbo Deng, NanNan Du, Pansong Li, Xuefeng Xia, Chengping Hu, Min Li","doi":"10.1007/s13402-023-00873-y","DOIUrl":"10.1007/s13402-023-00873-y","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor metastasis significantly impacts the prognosis of non-small cell lung cancer (NSCLC) patients, with lymph node (LN) metastasis being the most common and early form of spread. With the development of adjuvant immunotherapy, increasing attention has been paid to the tumor-draining lymph nodes（TDLN) in early-stage NSCLC, especially tumor-metastatic lymph nodes, which provides poor prognostic information but has potential benefits in adjuvant treatment.</p><p><strong>Methods: </strong>We showed the remodeled immune environment in TDLNs through using TCR-seq to analyse 24 primary lung cancer tissues and 134 LNs from 24 lung cancer patients with or without LN metastasis. Additionally, we characterized the spatial profiling of immunocytes and tumor cells in TDLNs and primary tumor sites through using multi-IHC.</p><p><strong>Results: </strong>We found the remodeled immune environment in TDLNs through analyzing primary lung cancer tissues and LNs from NSCLC patients with or without LN metastasis. Considering the intricate communication between tumor and immunocytes, we further subdivided TDLNs, revealing that metastasis-negative LNs from LN-metastatic patients (MNLN) exhibited greater immune activation, exhaustion, and memory in comparison to both metastasis-positive LNs (MPLN) and TDLNs from non-LN-metastatic patients (NMLN).</p><p><strong>Conclusions: </strong>Our data indicate that LN metastasis facilitated tumor-specific antigen presentation in TDLNs and induces T cell priming, while existing tumor cells generate an immune-suppressive environment in MPLNs through multiple mechanisms. These findings contribute to a comprehensive understanding of the immunological mechanisms through which LN metastasis influences tumor progression and plays a role in immunotherapy for NSCLC patients.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"447-461"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuropilin-2 acts a critical determinant for epithelial-to-mesenchymal transition and aggressive behaviors of human head and neck cancer.","authors":"Min-Hye Ahn, Ji-Hoon Kim, Su-Jung Choi, Hyun-Ji Kim, Dong-Guk Park, Kyu-Young Oh, Hye-Jung Yoon, Seong-Doo Hong, Jae-Il Lee, Ji-Ae Shin, Sung-Dae Cho","doi":"10.1007/s13402-023-00878-7","DOIUrl":"10.1007/s13402-023-00878-7","url":null,"abstract":"<p><strong>Purpose: </strong>Neuropilin-2 (NRP2) is a multifunctional single-pass transmembrane receptor that binds to two disparate ligands, namely, vascular endothelial growth factors (VEGFs) and semaphorins (SEMAs). It is reportedly involved in neuronal and vascular development. In this study, we uncovered the exact functional role of NRP2 and its molecular mechanism during aggressive behaviors and lymph node (LN) metastasis in human head and neck cancer (HNC) and identified algal methanol extract as a potential novel NRP2 inhibitor.</p><p><strong>Methods: </strong>In silico analyses and immunohistochemistry were used to investigate the relationship between NRP2 expression and the prognosis of HNC patients. The functional role of NRP2 on the proliferation, migration, invasion, and cancer stem cell (CSC) properties of HNC cells was examined by MTS, soft agar, clonogenic, transwell migration and invasion assays, and sphere formation assays. Signaling explorer antibody array, western blot, and qPCR were performed toward the investigation of a molecular mechanism that is related to NRP2.</p><p><strong>Results: </strong>NRP2 was highly expressed in HNC and positively correlated with LN metastasis and advanced tumor stage and size in patients. Using loss- or gain-of-function approaches, we found that NRP2 promoted the proliferative, migratory, and invasive capacities of human HNC cells. Furthermore, NRP2 regulated Sox2 expression to exhibit aggressiveness and CSC properties of human HNC cells. We demonstrated that p90 ribosomal S6 kinase 1 (RSK1) elevates the aggressiveness and CSC properties of human HNC cells, possibly by mediating NRP2 and Sox2. Zeb1 was necessary for executing the NRP2/RSK1/Sox2 signaling pathway during the induction of epithelial-to-mesenchymal transition (EMT) and aggressive behaviors of human HNC cells. Moreover, the methanol extract of Codium fragile (MECF) repressed NRP2 expression, inhibiting the RSK1/Sox2/Zeb1 axis, which contributed to the reduction of aggressive behaviors of human HNC cells.</p><p><strong>Conclusions: </strong>These findings suggest that NRP2 is a critical determinant in provoking EMT and aggressive behaviors in human HNC through the RSK1/Sox2/Zeb1 axis, and MECF may have the potential to be a novel NRP2 inhibitor for treating metastasis in HNC patients.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"497-511"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41162255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis.","authors":"Hong-Juan You, Li-Hong Ma, Xing Wang, Yu-Xin Wang, Huan-Yang Zhang, En-Si Bao, Yu-Jie Zhong, Xiang-Ye Liu, De-Long Kong, Kui-Yang Zheng, Fan-Yun Kong, Ren-Xian Tang","doi":"10.1007/s13402-023-00889-4","DOIUrl":"10.1007/s13402-023-00889-4","url":null,"abstract":"<p><strong>Purpose: </strong>As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC.</p><p><strong>Methods: </strong>Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC.</p><p><strong>Results: </strong>We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells.</p><p><strong>Conclusions: </strong>These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"639-655"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Notum enhances gastric cancer stem-like cell properties through upregulation of Sox2 by PI3K/AKT signaling pathway.","authors":"Yi Liu, Hui Chen, Lanshu Xiao, Ping Dong, Yanhui Ma, Yunlan Zhou, Junyao Yang, Bingxian Bian, Guohua Xie, Lei Chen, Lisong Shen","doi":"10.1007/s13402-023-00875-w","DOIUrl":"10.1007/s13402-023-00875-w","url":null,"abstract":"<p><strong>Purpose: </strong>Considerable evidence suggests that tumor cells with stemness features contribute to initiation, progression, recurrence of gastric cancer (GC) and resistance to therapy, but involvement of underlying regulators and mechanisms remain largely unclear. However, the clinical significance and biological function of Notum in GC tumor sphere formation and tumorigenesis remain unclear.</p><p><strong>Methods: </strong>Bioinformatics analysis, RT-qPCR, western blot and imunohistochemistry staining were applied to characterize Notum expression in GC specimens. The early diagnostic value of Notum was analyzed by logistic regression analysis method. Cancer stemness assays were used in Notum knockdown and overexpressing cells in vitro and in vivo. RNA-seq was employed to reveal the downstream effectors of Notum.</p><p><strong>Results: </strong>Notum is highly expressed in early stage of GC patients and stem-like GC cells. For discriminating the early-stage and advanced GC patients, the joint analysis had a better diagnostic value. Overexpression of Notum markedly increased stemness features of GC cells to promote tumor sphere formation and tumorigenesis. Conversely, Notum knockdown attenuated the stem-like cell properties in vitro and in vivo. Mechanically, Notum upregulates Sox2 through activating the PI3K/AKT signaling pathway. Notum inhibitor Caffeine exhibited a potent inhibitory effect on stemness features by impairing the PI3K/AKT signaling pathway activity and targeting Sox2.</p><p><strong>Conclusion: </strong>Our findings confer a comprehensive and mechanistic function of Notum in GC tumor sphere formation and tumorigenesis that may provide a novel and promising target for early diagnosis and clinical therapy of GC.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"463-480"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41136806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redox signaling-mediated tumor extracellular matrix remodeling: pleiotropic regulatory mechanisms.","authors":"Guowen Liu, Bowen Li, Siyuan Qin, Edouard C Nice, Jinlin Yang, Li Yang, Canhua Huang","doi":"10.1007/s13402-023-00884-9","DOIUrl":"10.1007/s13402-023-00884-9","url":null,"abstract":"<p><strong>Background: </strong>The extracellular matrix (ECM), a fundamental constituent of all tissues and organs, is crucial for shaping the tumor microenvironment. Dysregulation of ECM remodeling has been closely linked to tumor initiation and progression, where specific signaling pathways, including redox signaling, play essential roles. Reactive oxygen species (ROS) are risk factors for carcinogenesis whose excess can facilitate the oxidative damage of biomacromolecules, such as DNA and proteins. Emerging evidence suggests that redox effects can aid the modification, stimulation, and degradation of ECM, thus affecting ECM remodeling. These alterations in both the density and components of the ECM subsequently act as critical drivers for tumorigenesis. In this review, we provide an overview of the functions and primary traits of the ECM, and it delves into our current understanding of how redox reactions participate in ECM remodeling during cancer progression. We also discuss the opportunities and challenges presented by clinical strategies targeting redox-controlled ECM remodeling to overcome cancer.</p><p><strong>Conclusions: </strong>The redox-mediated ECM remodeling contributes importantly to tumor survival, progression, metastasis, and poor prognosis. A comprehensive investigation of the concrete mechanism of redox-mediated tumor ECM remodeling and the combination usage of redox-targeted drugs with existing treatment means may reveal new therapeutic strategy for future antitumor therapies.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"429-445"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploration of molecular markers related to chemotherapy efficacy of hepatoid adenocarcinoma of the stomach.","authors":"Jingtao Wei, Ke Ji, Yue Zhang, Ji Zhang, Xiaojiang Wu, Xin Ji, Kai Zhou, Xuesong Yang, Hongfeng Lu, Anqiang Wang, Zhaode Bu","doi":"10.1007/s13402-023-00892-9","DOIUrl":"10.1007/s13402-023-00892-9","url":null,"abstract":"<p><strong>Purpose: </strong>Preoperative neoadjuvant chemotherapy may not improve the prognosis of patients with hepatoid adenocarcinoma of the stomach (HAS), a rare pathological type of gastric cancer. Thus, the study aimed at the genomic and transcriptomic impacts of preoperative chemotherapy on HAS.</p><p><strong>Methods: </strong>Patients with HAS who underwent surgical resection at Peking University Cancer Hospital were retrospectively included in this study. Whole exome sequencing and transcriptome sequencing were performed on pre-chemotherapy, non-chemotherapy and post-chemotherapy samples. We then compared the alterations in molecular markers between the post-chemotherapy and non-chemotherapy groups, and between the chemotherapy-effective and chemotherapy-ineffective groups, respectively.</p><p><strong>Results: </strong>A total of 79 tumor samples from 72 patients were collected. Compared to the non-chemotherapy group, the mutation frequencies of several genes were changed after chemotherapy, including TP53. In addition, there was a significant increase in the frequency of frameshift mutations and cytosine transversion to adenine (C > A), appearance of COSMIC signature 6 and 14, and a reduced gene copy number amplification. Interestingly, the same phenomenon was observed in chemotherapy-ineffective patients. In addition, many HAS patients had ERBB2, FGFR2, MET and HGF gene amplification. Moreover, the expression of immune-related genes, especially those related to lymphocyte activation, was down-regulated after chemotherapy.</p><p><strong>Conclusion: </strong>Chemotherapy is closely associated with changes in the molecular characteristics of HAS. After chemotherapy, at genomic and transcriptome level, many features were altered. These changes may be molecular markers of poor chemotherapeutic efficacy and play an important role in chemoresistance in HAS. In addition, ERBB2, FGFR2, MET and HGF gene amplification may be potential therapeutic targets for HAS.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"677-693"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the lipid metabolic reprogramming of tumor-associated macrophages: A novel insight into cancer immunotherapy.","authors":"Liang Li, Si-Rui Ma, Zi-Li Yu","doi":"10.1007/s13402-023-00881-y","DOIUrl":"10.1007/s13402-023-00881-y","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated macrophages, as the major immunocytes in solid tumors, show divided loyalty and remarkable plasticity in tumorigenesis. Once the M2-to-M1 repolarization is achieved, they could be switched from the supporters for tumor development into the guardians for host immunity. Meanwhile, Lipid metabolic reprogramming is demonstrated to be one of the most important hallmarks of tumor-associated macrophages, which plays a decisive role in regulating their phenotypes and functions to promote tumorigenesis and immunotherapy resistance. Therefore, targeting the lipid metabolism of TAMs may provide a new direction for anti-tumor strategies.</p><p><strong>Conclusion: </strong>In this review, we first summarized the origins, classifications and general lipid metabolic process of TAMs. Then we discussed the currently available drugs and interventions that target lipid metabolic disorders of TAMs, including those targeting lipid uptake, efflux, lipolysis, FAO and lipid peroxidation. Besides, based on the recent research status, we summarized the present challenges for this cancer immunotherapy, including the precise drug delivery system, the lipid metabolic heterogeneity, and the intricate lipid metabolic interactions in the TME, and we also proposed corresponding possible solutions. Collectively, we hope this review will give researchers a better understanding of the lipid metabolism of TAMs and lead to the development of corresponding anti-tumor therapies in the future.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"415-428"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41169397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complexation of histone deacetylase inhibitor belinostat to Cu(II) prevents premature metabolic inactivation in vitro and demonstrates potent anti-cancer activity in vitro and ex vivo in colon cancer.","authors":"Ellen Finnegan, Wei Ding, Ziga Ude, Sara Terer, Tadhg McGivern, Anna M Blümel, Grainne Kirwan, Xinxin Shao, Flavia Genua, Xiaofei Yin, Alexander Kel, Sarinj Fattah, Parvathi A Myer, Sally-Ann Cryan, Jochen H M Prehn, Darran P O'Connor, Lorraine Brennan, Gregory Yochum, Celine J Marmion, Sudipto Das","doi":"10.1007/s13402-023-00882-x","DOIUrl":"10.1007/s13402-023-00882-x","url":null,"abstract":"<p><strong>Purpose: </strong>The histone deacetylase inhibitor (HDACi), belinostat, has had limited therapeutic impact in solid tumors, such as colon cancer, due to its poor metabolic stability. Here we evaluated a novel belinostat prodrug, copper-bis-belinostat (Cubisbel), in vitro and ex vivo, designed to overcome the pharmacokinetic challenges of belinostat.</p><p><strong>Methods: </strong>The in vitro metabolism of each HDACi was evaluated in human liver microsomes (HLMs) using mass spectrometry. Next, the effect of belinostat and Cubisbel on cell growth, HDAC activity, apoptosis and cell cycle was assessed in three colon cancer cell lines. Gene expression alterations induced by both HDACis were determined using RNA-Seq, followed by in silico analysis to identify master regulators (MRs) of differentially expressed genes (DEGs). The effect of both HDACis on the viability of colon cancer patient-derived tumor organoids (PDTOs) was also examined.</p><p><strong>Results: </strong>Belinostat and Cubisbel significantly reduced colon cancer cell growth mediated through HDAC inhibition and apoptosis induction. Interestingly, the in vitro half-life of Cubisbel was significantly longer than belinostat. Belinostat and its Cu derivative commonly dysregulated numerous signalling and metabolic pathways while genes downregulated by Cubisbel were potentially controlled by VEGFA, ERBB2 and DUSP2 MRs. Treatment of colon cancer PDTOs with the HDACis resulted in a significant reduction in cell viability and downregulation of stem cell and proliferation markers.</p><p><strong>Conclusions: </strong>Complexation of belinostat to Cu(II) does not alter the HDAC activity of belinostat, but instead significantly enhances its metabolic stability in vitro and targets anti-cancer pathways by perturbing key MRs in colon cancer. Complexation of HDACis to a metal ion might improve the efficacy of clinically used HDACis in patients with colon cancer.</p>","PeriodicalId":49223,"journal":{"name":"Cellular Oncology","volume":" ","pages":"533-553"},"PeriodicalIF":6.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71487970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}