bioRxiv - Cancer Biology最新文献_第9页

Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells. 促进坏死蛋白 MLKL 失活会导致结直肠癌细胞出现治疗漏洞。

bioRxiv - Cancer Biology Pub Date : 2024-09-06 DOI: 10.1101/2024.09.05.611491

Peijia Jiang, Sandhya Chipurupalli, Byong Hoon Yoo, Xiaoyang Liu, Kirill V Rosen

{"title":"Inactivation of necroptosis-promoting protein MLKL creates a therapeutic vulnerability in colorectal cancer cells.","authors":"Peijia Jiang, Sandhya Chipurupalli, Byong Hoon Yoo, Xiaoyang Liu, Kirill V Rosen","doi":"10.1101/2024.09.05.611491","DOIUrl":"https://doi.org/10.1101/2024.09.05.611491","url":null,"abstract":"Mortality from colorectal cancer (CRC) is significant, and novel CRC therapies are needed. A pseudokinase MLKL typically executes necroptotic cell death, and MLKL inactivation protects cells from such death. However, we found unexpectedly that MLKL gene knockout enhanced CRC cell death caused by a protein synthesis inhibitor homoharringtonine used for chronic myeloid leukemia treatment. In an effort to explain this finding, we observed that MLKL gene knockout reduced CRC cell autophagy and rendered such autophagy critically dependent on the presence of VPS37A, a component of the ESCRT-I complex. Moreover, homoharringtonine-induced activation of p38 MAP kinase (p38MAPK) prevented VPS37A from supporting autophagy in MLKL-deficient cells and triggered their parthanatos, a cell death type driven by poly(ADP-ribose) polymerase hyperactivation. Finally, a pharmacological MLKL inhibitor necrosulfonamide strongly cooperated with homoharringtonine in suppressing CRC cell tumorigenicity in mice. Thus, while MLKL mediates necroptosis, MLKL protects CRC cells from death caused by drugs blocking basal autophagy, e.g., homoharringtonine, and MLKL inhibition creates a therapeutic vulnerability that could be utilized for CRC treatment.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells 基于图像的单细胞定量方法显示，与正常细胞相比，肿瘤细胞的全局染色质可及性有所增加

bioRxiv - Cancer Biology Pub Date : 2024-09-06 DOI: 10.1101/2024.09.05.611456

Mairead Commane, Vidula Jadhav, Katerina Leonova, Henry Withers, Brian Buckley, Katerina Gurova

{"title":"Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells","authors":"Mairead Commane, Vidula Jadhav, Katerina Leonova, Henry Withers, Brian Buckley, Katerina Gurova","doi":"10.1101/2024.09.05.611456","DOIUrl":"https://doi.org/10.1101/2024.09.05.611456","url":null,"abstract":"The phenotypic plasticity of cancer cells has recently emerged as an important factor of treatment failure. The mechanisms of phenotypic plasticity are not fully understood. One of the hypotheses is that the degree of chromatin accessibility defines the easiness of cell transitions between different phenotypes. To test this, a method to compare overall chromatin accessibility between cells in a population or between cell populations is needed. We propose to measure chromatin accessibility by fluorescence signal from nuclei of cells stained with DNA binding fluorescent molecules. This method is based on the observations that small molecules bind nucleosome-free DNA more easily than nucleosomal DNA. Thus, nuclear fluorescence is proportional to the amount of nucleosome-free DNA, serving as a measure of chromatin accessibility. We optimized the method using several DNA intercalators and minor groove binders and known chromatin-modulating agents and demonstrated that chromatin accessibility is increased upon oncogene-induced transformation and further in tumor cells.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer. HOXB6和HOXB8控制着胰腺癌中免疫细胞与癌细胞的相互作用。

bioRxiv - Cancer Biology Pub Date : 2024-09-06 DOI: 10.1101/2024.09.06.611619

Ludivine Bertonnier-Brouty, Kavya Achanta, Jonas Andersson, Sara Bsharat, Tania Singh, Tuomas Kaprio, Jaana Hagstrom, Caj Haglund, Hanna Seppanen, Rashmi B Prasad, Isabella Artner

{"title":"HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer.","authors":"Ludivine Bertonnier-Brouty, Kavya Achanta, Jonas Andersson, Sara Bsharat, Tania Singh, Tuomas Kaprio, Jaana Hagstrom, Caj Haglund, Hanna Seppanen, Rashmi B Prasad, Isabella Artner","doi":"10.1101/2024.09.06.611619","DOIUrl":"https://doi.org/10.1101/2024.09.06.611619","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer lacking effective drugs and therefore new treatment targets are needed. Transcriptomic analysis comparing human embryonic and PDAC tissue identified a large overlap of expression profiles suggesting a re-initiation of developmental programs in pancreatic cancer. Specifically, we identified the transcription factors HOXB6 and HOXB8 as potential key regulators in PDAC. Loss of HOXB6 and HOXB8 in pancreatic cancer cells inhibited cell proliferation, induced apoptosis and senescence and enhanced gemcitabine sensitivity. Moreover, reduced HOXB6 and HOXB8 expression in pancreatic and lung adenocarcinoma cell lines affected transcription of immune response pathways which resulted in an increased sensitivity of cancer cells to anti-tumorigenic activities of macrophages suggesting that the HOXB6 and HOXB8 immune regulatory pattern is conserved in different cancer types. Additionally, naive M0 macrophages exposed to HOXB8 deficient PDAC cells were unable to differentiate into tumor associated macrophages, suggesting that HOXB8 promotes the transition of initial anti-tumor macrophage to a tumor-promoting macrophage phenotype in pancreatic cancer. Our findings indicate that HOXB6 and HOXB8 play important roles in regulating cell proliferation, immune response and treatment resistance to promote pancreatic cancer tumorigenesis and could be useful therapeutic targets.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive analysis of the RBP regulome reveals functional modules and drug candidates in liver cancer 对 RBP 调节组的全面分析揭示了肝癌的功能模块和候选药物

bioRxiv - Cancer Biology Pub Date : 2024-09-06 DOI: 10.1101/2024.09.04.611258

Mateusz Garbulowski, Riccardo Mosca, Carlos J. Gallardo-Dodd, Claudia Kutter, Erik L. L. Sonnhammer

{"title":"Comprehensive analysis of the RBP regulome reveals functional modules and drug candidates in liver cancer","authors":"Mateusz Garbulowski, Riccardo Mosca, Carlos J. Gallardo-Dodd, Claudia Kutter, Erik L. L. Sonnhammer","doi":"10.1101/2024.09.04.611258","DOIUrl":"https://doi.org/10.1101/2024.09.04.611258","url":null,"abstract":"RNA binding proteins (RBPs) are essential components of the transcriptomic regulome. Identifying the RBP regulome in cancer cells is crucial to discovering and understanding carcinogenesis mechanisms and providing new therapeutic targets. Here, we aimed to reveal the regulome of liver cancer upon specific perturbations. To this end, we applied a consensus Gene Regulatory Network (GRN) approach using knockdown data for the liver cancer cell line HepG2. By incorporating multiple GRNs from diverse inference methods, we constructed a highly precise GRN. To validate our results, we comprehensively evaluated the consensus GRN, focusing on characterizing the most relevant aspects of the liver cancer regulome. This included utilizing eCLIP-seq and RAPseq data to verify RBP interactions and binding sites. In addition, we performed an enrichment analysis of network modules and drug repurposing based on the inferred GRN. Taken together, our findings demonstrate the critical roles of RBP regulatory interactions in liver cancer that can be employed to improve treatment strategies.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential gene expression in cells with different p53 mutations identifies genome-wide p53 targets and shows distinct modulation of cellular pathways in response to DNA damage 不同 p53 基因突变细胞中的差异基因表达确定了全基因组 p53 靶点，并显示了细胞通路在应对 DNA 损伤时的不同调节方式

bioRxiv - Cancer Biology Pub Date : 2024-09-06 DOI: 10.1101/2024.09.05.611436

Patricia Eror Barnes, Maria Jose de la Concha, Kioko Mwikali, Bee Ling Ng, Hannes Ponstingl, Alena Pance

{"title":"Differential gene expression in cells with different p53 mutations identifies genome-wide p53 targets and shows distinct modulation of cellular pathways in response to DNA damage","authors":"Patricia Eror Barnes, Maria Jose de la Concha, Kioko Mwikali, Bee Ling Ng, Hannes Ponstingl, Alena Pance","doi":"10.1101/2024.09.05.611436","DOIUrl":"https://doi.org/10.1101/2024.09.05.611436","url":null,"abstract":"The fundamental transcription factor p53 regulates cellular processes and integrates signals of cellular stress, triggering a coordinated response to ensure survival of cells restored to healthy function and programmed death of those that could not be repaired. Unsurprisingly, this is one of the most mutated genes in human cancers, with most changes occurring in the DNA-binding domain of the protein. In this work, we take a genome-wide approach and use available resources to identify high confidence p53-target genes, that we examine in three breast cancer cell lines with different p53 status, wild type (MCF-7) and different mutations in the DNA-binding domain (MDA-MB231, T47D). Comparison of p53-targets expression in response to DNA damage by RNAseq and cellular assays reveals that MDA-MB231 have a severely impaired p53-dependent pathway functionality while T47D are much less affected. MDA-MB231 are more resistant to DNA damage yet unable to repair and able to override cell cycle arrest leading to survival while T47D are sensitive only to high dose and exposure to genotoxic agents. This data shows the variability of effects of different p53 mutations and highlight the importance of understanding the mechanisms of p53 in the context of genotoxicity-based treatment.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy 用于个性化免疫疗法的自组装免疫特征骨肉瘤患者/PDX 衍生类器官模型和生物库

bioRxiv - Cancer Biology Pub Date : 2024-08-11 DOI: 10.1101/2024.08.11.607471

Haoran Mu, Yining Tao, Jinzeng Wang, Xin He, Qi Zhang, Weixi Chen, Bing Yao, Sen Ding, Xiyu Yang, Liyuan Zhang, Hongsheng Wang, Dongqing Zuo, Jiakang Shen, Mengxiong Sun, Haoyu Wang, Ming Jiao, Xinmeng Jin, Yinhui Jin, Youzhi Liang, Yuyan Gong, Winfred Mao, Qian Liu, Zhuoying Wang, Yu Lv, Jing Xu, Tao Zhang, Yuqin Yang, Jun Lin, Fred J. Asward, James D. Joseph, Mingxi Li, Zhengdong Cai, Wei Sun, Liu Yang, Yingqi Hua

{"title":"A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy","authors":"Haoran Mu, Yining Tao, Jinzeng Wang, Xin He, Qi Zhang, Weixi Chen, Bing Yao, Sen Ding, Xiyu Yang, Liyuan Zhang, Hongsheng Wang, Dongqing Zuo, Jiakang Shen, Mengxiong Sun, Haoyu Wang, Ming Jiao, Xinmeng Jin, Yinhui Jin, Youzhi Liang, Yuyan Gong, Winfred Mao, Qian Liu, Zhuoying Wang, Yu Lv, Jing Xu, Tao Zhang, Yuqin Yang, Jun Lin, Fred J. Asward, James D. Joseph, Mingxi Li, Zhengdong Cai, Wei Sun, Liu Yang, Yingqi Hua","doi":"10.1101/2024.08.11.607471","DOIUrl":"https://doi.org/10.1101/2024.08.11.607471","url":null,"abstract":"Osteosarcoma (OS) exhibit intra- and inter- heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Triple Negative Breast Cancer Cells Acquire Lymphocyte Proteins and Genomic DNA During Trogocytosis with T Cells 三阴性乳腺癌细胞在与 T 细胞的逆行吞噬过程中获得淋巴细胞蛋白和基因组 DNA

bioRxiv - Cancer Biology Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607029

Anutr Sivakoses, Haley Quinn Marcarian, Anika M Arias, Alice R Lam, Olivia C Ihedioha, Juan A Santamaria, Geoffrey C Gurtner, Alfred L. M. Bothwell

引用次数: 0

dia-PASEF Proteomics of Tumor and Stroma LMD Enriched from Archived HNSCC Samples 从归档 HNSCC 样品中富集的肿瘤和基质 LMD 的 dia-PASEF 蛋白质组学研究

bioRxiv - Cancer Biology Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607341

Aswini Panigrahi, Allison L Hunt, Diego Assis, Matthew Willetts, Bhaskar V Kallakury, Bruce Davidson, Thomas P Conrads, Radoslav Goldman

{"title":"dia-PASEF Proteomics of Tumor and Stroma LMD Enriched from Archived HNSCC Samples","authors":"Aswini Panigrahi, Allison L Hunt, Diego Assis, Matthew Willetts, Bhaskar V Kallakury, Bruce Davidson, Thomas P Conrads, Radoslav Goldman","doi":"10.1101/2024.08.09.607341","DOIUrl":"https://doi.org/10.1101/2024.08.09.607341","url":null,"abstract":"We employed laser microdissection to selectively harvest tumor cells and stroma from the microenvironment of formalin-fixed, paraffin-embedded head and neck squamous cell carcinoma (HNSCC) tissues. The captured HNSCC tissue fractions were analyzed by quantitative mass spectrometry-based proteomics using a data independent analysis approach. In paired samples, we achieved excellent proteome coverage having quantified 6,668 proteins with a median quantitative coefficient of variation under 10%. We observed significant differences in relevant functional pathways between the spatially resolved tumor and stroma regions. Our results identified extracellular matrix (ECM) as a major component enriched in the stroma, including many cancer associated fibroblast signature proteins in this compartment. We demonstrate the potential for comparative deep proteome analysis from very low starting input in a scalable format that is useful to decipher the alterations in tumor and the stromal microenvironment. Correlating such results with clinical features or disease progression will likely enable identification of novel targets for disease classification and interventions.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pyruvate from bone marrow mesenchymal stem cells supports myeloma redox homeostasis and anabolism 骨髓间充质干细胞产生的丙酮酸支持骨髓瘤的氧化还原平衡和合成代谢

bioRxiv - Cancer Biology Pub Date : 2024-08-09 DOI: 10.1101/2024.08.08.607157

Elías Vera-Sigüenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Charlotte Speakman, Alejandro Huerta-Uribe, Lisa Vettore, Himani Rana, Adam Boufersaoui, Hans Vellama, Ramin Nashebi, Ielyaas Cloete, Jennie Roberts, Supratik Basu, Mark Drayson, Christopher Bunce, Guy Pratt, Fabian Spill, Oliver D.K. Maddocks, Daniel A. Tennant

{"title":"Pyruvate from bone marrow mesenchymal stem cells supports myeloma redox homeostasis and anabolism","authors":"Elías Vera-Sigüenza, Cristina Escribano-Gonzalez, Irene Serrano-Gonzalo, Kattri-Liis Eskla, Charlotte Speakman, Alejandro Huerta-Uribe, Lisa Vettore, Himani Rana, Adam Boufersaoui, Hans Vellama, Ramin Nashebi, Ielyaas Cloete, Jennie Roberts, Supratik Basu, Mark Drayson, Christopher Bunce, Guy Pratt, Fabian Spill, Oliver D.K. Maddocks, Daniel A. Tennant","doi":"10.1101/2024.08.08.607157","DOIUrl":"https://doi.org/10.1101/2024.08.08.607157","url":null,"abstract":"Multiple myeloma is an incurable cancer of plasma cells that depends on the bone marrow for its survival. Despite its prevalence, the molecular mechanisms underlying this malignancy remain poorly understood. In this study, we aim to bridge this knowledge gap by elucidating the metabolic interplay between myeloma cells and bone marrow mesenchymal stem cells (BMMSCs). BMMSCs are crucial in supporting myeloma cell metabolism, contributing to their proliferation, survival, and resistance to chemotherapy. Through a combination of mathematical modelling and experimental co-cultures, we demonstrate that pyruvate – the end product of glycolysis – plays a key role in myeloma cell metabolism. Our findings reveal that myeloma cells predominantly rely on the uptake of pyruvate produced by neighbouring BMM-SCs via the plasma membrane proton-linked monocarboxylate transporters MCT-1 and MCT-2 encoded by the Slc16a1 and a2 genes, respectively. Furthermore, we show that pharmacological inhibition of the MCT-1/2, with AZD3965, triggers a cascade of compensatory metabolic responses, disrupting redox balance and significantly reducing the proliferation capacity of co-cultured myeloma cells.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimized LC-MS/MS method for Doxorubicin quantification: validating drug uptake and tumor reduction in zebrafish xenograft model of breast cancer 优化的多柔比星定量 LC-MS/MS 方法：验证斑马鱼乳腺癌异种移植模型的药物吸收和肿瘤缩小情况

bioRxiv - Cancer Biology Pub Date : 2024-08-09 DOI: 10.1101/2024.08.09.607268

Ghazala Rahman, Atanu Pramanik, Susmita Das, Anindya Roy, Anamika Bhargava

{"title":"Optimized LC-MS/MS method for Doxorubicin quantification: validating drug uptake and tumor reduction in zebrafish xenograft model of breast cancer","authors":"Ghazala Rahman, Atanu Pramanik, Susmita Das, Anindya Roy, Anamika Bhargava","doi":"10.1101/2024.08.09.607268","DOIUrl":"https://doi.org/10.1101/2024.08.09.607268","url":null,"abstract":"Doxorubicin, a potent chemotherapeutic drug, is widely used against various cancers, notably breast cancer. While its efficacy is well-documented, precise dosage determination in experimental models remains challenging. Zebrafish xenografts of various cancers confirm doxorubicin's anti-cancerous effect; however, since doxorubicin treatment of zebrafish larva is done by adding doxorubicin to fish water, the precise chemotherapeutic dosage for zebrafish larva remains unknown. In this study, we provide a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for quantifying doxorubicin uptake in zebrafish larvae and thus provide a direct estimate of doses required for the therapeutic effect. Alongside quantification, we measured the therapeutic effect of doxorubicin in zebrafish larvae xenografted with triple negative breast cancer cell line, MDA-MB-231. LD50 value of doxorubicin was first determined by incubating 3-days post fertilization (dpf) larvae with different doses of doxorubicin for 72 h. Doxorubicin was quantified both from zebrafish larval homogenate and treatment solution. Analysis was performed by selected-reaction monitoring (SRM) scans in positive ionization mode. LD50 value for 72 h calculated to be 35.95 mg/L. As expected, doxorubicin-treated xenografts exhibited a significant reduction in tumor growth. The range of limit of detection (LOD) and limit of quantification (LOQ) for doxorubicin were 2 and 5 μg/L respectively. Intra- and inter-day accuracy was within the range of 82-114%. Overall, in this study we describe a reliable method for quantifying doxorubicin in zebrafish larvae. Our study facilitates precise dosage estimation, enhancing the relevance of zebrafish xenograft model in cancer research and potentially improving translational applications of chemotherapeutic treatments.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0