癌症耐药(英文)最新文献

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Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the "Cancer Stem Cells and Drug Resistance". 癌症干细胞的耐药性:介绍电子书覆盖的特刊“癌症干细胞和耐药性”。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.23
Balázs Sarkadi
{"title":"Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the \"Cancer Stem Cells and Drug Resistance\".","authors":"Balázs Sarkadi","doi":"10.20517/cdr.2023.23","DOIUrl":"https://doi.org/10.20517/cdr.2023.23","url":null,"abstract":"© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"239-241"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication? 急性髓性白血病(AML)如何从fms相关酪氨酸激酶3 (FLT3)抑制剂中逃脱?还是一个被高估的并发症?
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.130
Salvatore Perrone, Tiziana Ottone, Nadezda Zhdanovskaya, Matteo Molica
{"title":"How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?","authors":"Salvatore Perrone,&nbsp;Tiziana Ottone,&nbsp;Nadezda Zhdanovskaya,&nbsp;Matteo Molica","doi":"10.20517/cdr.2022.130","DOIUrl":"https://doi.org/10.20517/cdr.2022.130","url":null,"abstract":"<p><p>FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1<sup>st</sup> and 2<sup>nd</sup> generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"223-238"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Importance of ROS1 gene fusions in non-small cell lung cancer. ROS1基因融合在非小细胞肺癌中的重要性。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.105
Meri Muminovic, Carlos Rodrigo Carracedo Uribe, Andres Alvarez-Pinzon, Khine Shan, Luis E Raez
{"title":"Importance of <i>ROS1</i> gene fusions in non-small cell lung cancer.","authors":"Meri Muminovic,&nbsp;Carlos Rodrigo Carracedo Uribe,&nbsp;Andres Alvarez-Pinzon,&nbsp;Khine Shan,&nbsp;Luis E Raez","doi":"10.20517/cdr.2022.105","DOIUrl":"https://doi.org/10.20517/cdr.2022.105","url":null,"abstract":"Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"332-344"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
miR-16-5p enhances sensitivity to RG7388 through targeting PPM1D expression (WIP1) in Childhood Acute Lymphoblastic Leukemia. miR-16-5p通过靶向儿童急性淋巴细胞白血病中PPM1D表达(WIP1)增强对RG7388的敏感性。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.113
Maryam Zanjirband, Soheila Rahgozar, Narges Aberuyi
{"title":"miR-16-5p enhances sensitivity to RG7388 through targeting <i>PPM1D</i> expression (WIP1) in Childhood Acute Lymphoblastic Leukemia.","authors":"Maryam Zanjirband,&nbsp;Soheila Rahgozar,&nbsp;Narges Aberuyi","doi":"10.20517/cdr.2022.113","DOIUrl":"https://doi.org/10.20517/cdr.2022.113","url":null,"abstract":"<p><p><b>Aim:</b> Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). <b>Methods:</b> miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. <b>Results:</b> MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21<sup>WAF1</sup> and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. <b>Conclusion:</b> This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"242-256"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities. 具有微管不稳定、抗血管生成和myb抑制活性的多模态4-芳基铬衍生物。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.90
Leonhard H F Köhler, Sebastian Reich, Maria Yusenko, Karl-Heinz Klempnauer, Gerrit Begemann, Rainer Schobert, Bernhard Biersack
{"title":"Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities.","authors":"Leonhard H F Köhler,&nbsp;Sebastian Reich,&nbsp;Maria Yusenko,&nbsp;Karl-Heinz Klempnauer,&nbsp;Gerrit Begemann,&nbsp;Rainer Schobert,&nbsp;Bernhard Biersack","doi":"10.20517/cdr.2022.90","DOIUrl":"https://doi.org/10.20517/cdr.2022.90","url":null,"abstract":"<p><p><b>Aim:</b> Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. <b>Methods:</b> 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. <b>Results:</b> Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation <i>in vivo</i>. <b>Conclusion:</b> The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 1","pages":"59-77"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9317813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance. 真菌菌群介导的免疫反应:胰腺肿瘤发生和化疗耐药的不可忽视的启动子。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.06
Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng
{"title":"Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance.","authors":"Yaling Jiang,&nbsp;Valentina Donati,&nbsp;Godefridus J Peters,&nbsp;Elisa Giovannetti,&nbsp;Dong Mei Deng","doi":"10.20517/cdr.2023.06","DOIUrl":"https://doi.org/10.20517/cdr.2023.06","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam <i>et al.</i> discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"284-290"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9823119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells. 孕激素X受体与缺氧诱导因子-1的相互作用调控前列腺癌细胞的化疗耐药。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.14
Jiuhui Wang, Daotai Nie
{"title":"Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells.","authors":"Jiuhui Wang,&nbsp;Daotai Nie","doi":"10.20517/cdr.2023.14","DOIUrl":"https://doi.org/10.20517/cdr.2023.14","url":null,"abstract":"<p><p><b>Aim:</b> The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance. <b>Methods:</b> Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance. <b>Results:</b> PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors. <b>Conclusion:</b> PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 2","pages":"378-389"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance. 用多西紫杉醇靶向激素抗性乳腺癌细胞:抗性内部观察。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.96
Alexander M Scherbakov, Anna A Basharina, Danila V Sorokin, Ekaterina I Mikhaevich, Iman E Mizaeva, Alexandra L Mikhaylova, Tatiana A Bogush, Mikhail A Krasil'nikov
{"title":"Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance.","authors":"Alexander M Scherbakov,&nbsp;Anna A Basharina,&nbsp;Danila V Sorokin,&nbsp;Ekaterina I Mikhaevich,&nbsp;Iman E Mizaeva,&nbsp;Alexandra L Mikhaylova,&nbsp;Tatiana A Bogush,&nbsp;Mikhail A Krasil'nikov","doi":"10.20517/cdr.2022.96","DOIUrl":"https://doi.org/10.20517/cdr.2022.96","url":null,"abstract":"<p><p><b>Aim:</b> The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. <b>Methods:</b> The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. <b>Results:</b> The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (<i>P</i> < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC<sub>50</sub> value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (<i>P</i> < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. <b>Conclusion:</b> Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 1","pages":"103-115"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport. p -糖蛋白(ABCB1) -弱偶极相互作用为理解同种异体识别、结合和运输提供了关键。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.59
Anna Seelig, Xiaochun Li-Blatter
{"title":"P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport.","authors":"Anna Seelig,&nbsp;Xiaochun Li-Blatter","doi":"10.20517/cdr.2022.59","DOIUrl":"https://doi.org/10.20517/cdr.2022.59","url":null,"abstract":"P-glycoprotein (ABCB1) is the first discovered mammalian member of the large family of ATP binding cassette (ABC) transporters. It facilitates the movement of compounds (called allocrites) across membranes, using the energy of ATP binding and hydrolysis. Here, we review the thermodynamics of allocrite binding and the kinetics of ATP hydrolysis by ABCB1. In combination with our previous molecular dynamics simulations, these data lead to a new model for allocrite transport by ABCB1. In contrast to previous models, we take into account that the transporter was evolutionarily optimized to operate within a membrane, which dictates the nature of interactions. Hydrophobic interactions drive lipid-water partitioning of allocrites, the transport process’s first step. Weak dipolar interactions (including hydrogen bonding, π-π stacking, and π-cation interactions) drive allocrite recognition, binding, and transport by ABCB1 within the membrane. Increasing the lateral membrane packing density reduces allocrite partitioning but enhances dipolar interactions between allocrites and ABCB1. Allocrite flopping (or reorientation of the polar part towards the extracellular aqueous phase) occurs after hydrolysis of one ATP molecule and opening of ABCB1 at the extracellular side. Rebinding of ATP re-closes the transporter at the extracellular side and expels the potentially remaining allocrite into the membrane. The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface. The proposed unidirectional ABCB1 transport cycle, driven by weak dipolar interactions, is consistent with membrane biophysics.","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 1","pages":"1-29"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9693650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Anti-BCMA novel therapies for multiple myeloma. 抗bcma治疗多发性骨髓瘤的新疗法。
癌症耐药(英文) Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.138
Vincenzo Sammartano, Marta Franceschini, Sara Fredducci, Federico Caroni, Sara Ciofini, Paola Pacelli, Monica Bocchia, Alessandro Gozzetti
{"title":"Anti-BCMA novel therapies for multiple myeloma.","authors":"Vincenzo Sammartano,&nbsp;Marta Franceschini,&nbsp;Sara Fredducci,&nbsp;Federico Caroni,&nbsp;Sara Ciofini,&nbsp;Paola Pacelli,&nbsp;Monica Bocchia,&nbsp;Alessandro Gozzetti","doi":"10.20517/cdr.2022.138","DOIUrl":"https://doi.org/10.20517/cdr.2022.138","url":null,"abstract":"<p><p>Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals; however, the prognosis remains poor. The BCMA antigen is highly expressed in myeloma cells, thus representing a target for novel therapies. Several agents that target BCMA through different mechanisms, including bispecific T cell engagers drug conjugated to antibody and CAR-T cells, are now available or under development. Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy. This review will discuss the recent development of anti-BCMA targeted treatments in myeloma, with a special focus on currently available agents.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 1","pages":"169-181"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
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