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Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

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oncology Research 2024年第4期32卷 769-784页

作者： HUAN GAO JIE ZHANG TONY GKLEIJN ZHAOYONG WU BING LIU YUJIN MA BAOYUE DING DONGFENG YIN Jiaxing Key Laboratory for Photonanomedicine and experimental Therapeutics Department of PharmaceuticsCollege of MedicineJiaxing UniversityJiaxing314001China department of Pharmacy The General Hospital of Xinjiang Military RegionUrumqi830000China department of Pathology and Medical biology University Medical Center GroningenUniversity of GroningenGroningen9713 GZThe Netherlands department of Pathology Laboratory of Experimental OncologyErasmus MCRotterdam3015 GDThe Netherlands department of Pharmacy Jiaxing Maternal and Child Health Care HospitalAffiliated Hospital of Jiaxing UniversityJiaxing314001China Qinghai Enlu Biotechnology Co. Ltd.Haidong810700China

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and *** treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic *** improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone ***(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size *** in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX *** micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated *** binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis *** vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic *** conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

关键词： Pluronic micelles Targeted nanotherapeutics Nanoparticulate drug delivery system Breast cancer with bone metastasis Therapeutic efficacy

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Histone deacetylase inhibitors for treatment of hepatocellular carcinoma

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Acta Pharmacologica Sinica 2005年第9期26卷 1025-1033页

作者： Danila CORADINI Annalisa SPERANZA uo tumor biology and experimental therapy department of experimental oncology Istituto Nazionale per lo Studio e la Cura dei tumori 20133 Milan Italy uo tumor biology and experimental therapy department of experimental oncology Istituto Nazionale per lo Studio e la Cura dei tumori 20133 Milan Italy

Hepatocellular carcinoma(HCC)is one of the most common cancers in the *** resection has been considered the optimal treatment approach,but onlya small proportion of patients are suitable candidates for surgery,and the relapserate is *** to prevent recurrence,including chemoemboliza-tionbefore and adjuvant therapy after surgery,have proven to have a limited benefit;liver transplantation is successful in treating limited-stage HCC because only aminority of patients qualify for ***,new therapeutic strat-egies are urgently *** in addition to the classical genetic mecha-nisms of deletion or inactivating point mutations,epigenetic alterations,such ashyperacetylation of the chromatin-associated histones(responsible for genesilencing),are believed to be involved in the development and progression ofHCC,novel compounds endowed with a histone deacetylase(HDAC)inhibitoryactivity are an attractive therapeutic *** particular,pre-clinical resultsobtained using HA-But,an HDAC inhibitor in which butyric acid residues areesterified to a hyaluronic acid backbone and characterized by a high affinity forthe membrane receptor CD44,indicated that this class of compounds may repre-sent a promising approach for hepatocellular carcinoma treatment.

关键词： hepatocellular carcinoma histone deace-tylase inhibitors cancer therapy

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

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Signal Transduction and Targeted therapy 2024年第8期9卷 3519-3532页

作者： Alvaro Quintanal-Villalonga Kenta Kawasaki Esther Redin Fathema Uddin Swanand Rakhade Vidushi Durani Amin Sabet Moniquetta Shafer Wouter R.Karthaus Samir Zaidi Yingqian A.Zhan Parvathy Manoj Harsha Sridhar Dennis Kinyua Hong Zhong Barbara P.Mello Metamia Ciampricotti Umesh K.Bhanot Irina Linkov Juan Qiu Radhika A.Patel Colm Morrsey Sanjoy Mehta Jesse Barnes Michael C.Haffner Nichlas D.Socci Richard P.Koche Elisa de Stanchina Sonia Molina-Pinelo Sohrab Salehi Helena A.Yu Joseph M.Chan Charles M.Rudin department of Medicine Thoracic Oncology ServiceMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Cancer biology and Genetics Program Sloan Kettering InstituteMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Vagelos College of Physicians and Surgeons Columbia UniversityNew YorkNYUSA Weill Cornell Graduate School of Medical Sciences Weill Cornell MedicineNew YorkNYUA Human oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Center for Epigenetics Research Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Pathology Core Facilty Department of Pathology and Laboratory MedicineMSKCCNew YorkNYUSA Antitumor Assessment Core Memorial Sloan Kettering Cancer CenterNew YorkNYUSA Divisionsof Human biology and Clinical Research Fred Hutchinon Cancer CenterSeattleWAUSA Deparmentof Urology University of WashingtonSeattleWAUSA Gene Editing&Screening Core Facility Memorial Sloan Kettering Cancer Center New YorkNYUSA department of Laboratory Medicine and Pathology University of WashingtonSeattleWAUSA Bioinfomatics CoreFacility Memorial Soan Kettering Cancer CenterNew YorkNYUSA Institute of Biomedicine of Seille(Bis) HURCSCUniversidad de SevillaSevilleSpain Computational oncology Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA Well Cornell Medical College New York NYUSA Present address:Swiss Institute for experimental Cancer Research(ISREC) School of Life SciencesEPFLLausanneSwitzerland

Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor *** to date,even if patients at high risk of transformation can be identified by the occurrence of tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological *** of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor ***7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological *** overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of ***7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma *** results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after *** simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.

关键词： tumors markedly transformation

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Targeting hormone-resistant breast cancer cells with docetaxel:a look inside the resistance

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Cancer Drug Resistance 2023年第1期6卷 103-115页

作者： 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 department of experimental tumor biology Blokhin N.N.National Medical Research Center of OncologyMoscow 115522Russian Federation Group of Molecular tumor Markers Blokhin N.N.National Medical Research Center of OncologyMoscow 115522Russian Federation

Aim: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 ***:The analysis of cell viability was performed by the MTT *** expression of signaling proteins was analyzed by immunoblotting and flow ***αactivity was evaluated by gene reporter *** establish hormone-resistant subline MCF7,breast cancer cells were treated with 4-hydroxytamoxifen for 12 ***:The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen,and the resistance index was *** Akt activity(2.2-fold)and decreased ERαexpression(1.5-fold)were revealed in MCF7/HT *** activity of the estrogen receptorαwas reduced(1.5-fold)in MCF7/*** of class Ⅲβ-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(Ptherapy for hormone-resistant cancer looks highly promising,especially for cancers with low TUBB3 expression.

关键词： Cancer docetaxel 4-hydroxytamoxifen classⅢβ-tubulin resistance breast cancer estrogen receptors alpha

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Incidence of human papilloma virus in esophageal squamous cell carcinoma in patients from the Lublin region

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World Journal of Gastroenterology 2012年第40期18卷 5739-5744页

作者： Andrzej Dabrowski Wojciech Kwasniewski Tomasz Skoczylas Wiesawa Bednarek Dorota Kuzma Anna Gozdzicka-Józefiak Second department of General and Gastrointestinal Surgery Oncological Surgery of the Alimentary TractMedical University of Lublin department of Gynecological oncology and Gynecology Medical University of Lublin department of Molecular Virology Institute of Experimental BiologyAdam Mickiewicz University

AIM:To assess the prevalence of human papilloma virus(HPV) in esophageal squamous cell carcinoma(ESCC) in the south-eastern region of ***:The study population consisted of 56 ESCC patients and 35 *** controls were patients referred to our department due to other nonesophageal and non-oncological disorders with no gross or microscopic esophageal pathology as confirmed by endoscopy and *** the ESCC patients,samples were taken from normal mucosa(56 mucosa samples) and from the tumor(56 tumor samples).Tissue samples from the controls were taken from normal mucosa of the middle esophagus(35 control samples).Quantitative determination of DNA was carried out using a spectrophotometric *** DNA was isolated using the QIAamp DNA Midi *** infection was identified following PCR amplification of the HPV gene sequence,using primers MY09 and MY11 complementary to the genome sequence of at least 33 types of *** sequencing results were computationally analyzed using the basic local alignment search tool ***:In tumor samples,HPV DNA was identified in 28 of 56 patients(50%).High risk HPV phenotypes(16 or/and 18) were found in 5 of 56 patients(8.9%),low risk in 19 of 56 patients(33.9%) and other types of HPV(37,81,97,CP6108) in 4 of 56 patients(7.1%).In mucosa samples,HPV DNA was isolated in 21 of 56 patients(37.5%).High risk HPV DNA was confirmed in 3 of 56 patients(5.3%),low risk HPV DNA in 12 of 56 patients(21.4%),and other types of HPV in 6 of 56 patients(10.7%).In control samples,HPV DNA was identified in 4 of 35 patients(11.4%) with no high risk *** occurrence of HPV in ESCC patients was significantly higher than in the controls [28 of 56(50%) vs 4 of 35(11.4%),P tumor and mucosa samples,the predominant HPV phenotypes were low risk HPV,isolated 4 times more frequently than high risk phenotypes [19 of 56(33.9%) vs 5 of 56(8.9%),P < 0.001].A higher prevalence of HPV

关键词： Human papilloma virus Low risk pheno-types High risk phenotypes Esophageal cancer Squa-mous cell carcinoma Carcinogenesis

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SUMOylation regulates p27^(Kip1) stability and localization in response to TGFβ

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分子细胞生物学报:英文版 2016年第1期8卷 17-30页

作者： Sara Lovisa Simona Citro Maura Sonego Alessandra Dall’Acqua Valentina Ranzuglia Stefania Berton Alfonso Colombatti Barbara Belletti Susanna Chiocca Monica Schiappacassi Gustavo Baldassarre Division of experimental oncology 2 Centro di Riferimento Oncologico National Cancer InstituteAviano 33081Italy department of experimental oncology European Institute of Oncology at the IFOM-IEO CampusMilan 20139Italy department of Scienze e Tecnologie Biomediche MATI Center of ExcellenceUniversity of UdineUdine 33010Italy Present address:department of Cancer biology Metastasis Research CenterThe University of Texas MD Anderson Cancer CenterHoustonTX 77030USA.

Exposure of normal and tumor-derived cells to TGFbresults in different outcomes,depending on the regulation of key *** CDK inhibitor p27^(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle *** treatment inhibits p27^(Kip1) degradation and induces its nuclear translocation,through mechanisms that are still *** evidences suggest that SUMOylation,a post-translational modification able to modulate the stability and subcellular localization of target proteins,critically modifies members of the TGFβ signaling ***,we demonstrate that p27^(Kip1) is SUMOylated in response to TGFβ *** different p27^(Kip1) point mutants,we identified lysine 134(K134)as the residue modified by small ubiquitin-like modifier 1(SUMO1)in response to TGFb ***β-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27^(Kip1).We observed thatSUMOylation regulated p27^(Kip1) binding to CDK2,thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine ***,p27^(Kip1) SUMOylation was necessary for proper cell cycle exit following *** data indicate thatSUMOylation is a novel regulatory mechanism that modulates p27^(Kip1) function in response to TGFβ *** the involvement of TGFb signaling in cancer cell proliferation and invasion,our data may shed light on an important aspect of this pathway during tumor progression.

关键词： p^(27kip1) SUMOylation TGFβ

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Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics

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Cancer biology & Medicine 2019年第2期16卷 247-263页

作者： Jelena Grahovac Tatjana Srdic-Rajic Juan Francisco Santibanez Marijana Pavlovic Milena Cavic Sinisa Radulovic1 Laboratory for experimental Pharmacology Institute for Oncology and Radiology of Serbia Belgrade 11000 Serbia department of Molecular oncology Institute for Medical Research University of Belgrade Belgrade 11000 Serbia Integrative Center for biology and Applied Chemistry (CIBQA) Bernardo O'Higgins University Santiago 8370854 Chile

Objective: Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPARγ, on melanoma cells as a potential agent for repurposing in melanoma ***: Expression of AGTR1 and PPARγ m RNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index ***: Both AGTR1 and PPARγ mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, we found that telmisartan decreased melanoma cell viability by inducing cell *** glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib in vitro, and even sensitized vemurafenib-resistant cells to the ***: Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.

关键词： Melanoma telmisartan apoptosis mitochondria reactive oxygen species targeted therapy

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Case of pancreatic metastasis from colon cancer in which cell block using the Trefle^■ endoscopic scraper enables differential diagnosis from pancreatic cancer

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World Journal of Gastrointestinal oncology 2018年第3期10卷 91-95页

作者： Akihisa Kato Itaru Naitoh Hiroyuki Kato Kazuki Hayashi Katsuyuki Miyabe Michihiro Yoshida Yasuki Hori Makoto Natsume Naruomi Jinno Takeshi Yanagita Shuji Takiguchi Satoru Takahashi Takashi Joh department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences department of experimental Pathology and tumor biology Nagoya City University Graduate School of Medical Sciences department of Gastroenterological Surgery Nagoya City University Graduate School of Medical Sciences

Endoscopic transpapillary brush cytology and forceps biopsy during endoscopic retrograde cholangiopancreatology are generally used to obtain pathological evidence of biliary strictures. Recently, the new endoscopic scraper Trefle~? has been reported and demonstrated high cancer detectability in malignant biliary strictures. This device is used to scrape the stricture over the guidewire, and, in the original method, the tissue and/or cell samples obtained are subjected to histological and/or cytological analysis separately. However, discrimination of chunks of tissue is hampered by the opacity of the surrounding fluid. We have developed a cell block technique for the Trefle~? device without dividing obtained specimens into tissue and cellular components, which is the simplest method and enables immunohistochemical analysis. We present a case of obstructive jaundice diagnosed immunohistochemically as pancreatic metastasis from colon cancer using cell block sections obtained with the Trefle~? device, which procedure is as easy as conventional brush cytology.

关键词： Trefle? Cell block Endoscopic scraper Pancreatic metastasis Biliary strictures

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A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma

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癌症 2015年第12期34卷 563-572页

作者： Fu-Tuo Feng Qian Cui Wen-Sheng Liu Yun-Miao Guo Qi-Sheng Feng Li-Zhen Chen Miao Xu Bing Luo Da-Jiang Li Li-Fu Hu Jaap M.Middeldorp Octavia Ramayanti Qian Tao Su-Mei Cao Wei-Hua Jia Jin-Xin Bei Yi-Xin Zeng Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer Medicine department of Pathology VU University Medical Center department of Medical Microbiology Qingdao University Medical College department of experimental Research Sun Yat-sen University Cancer Center department of Microbiology Tumor and Cell BiologyKarolinska Institute department of Clinical oncology The Chinese University of Hong Kong department of Epidemiology Cancer Prevention CenterSun Yat-sen University Cancer Center

Background:Epstein-Barr virus(EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma(NPC),which has a high incidence in certain *** study aimed to address how EBV variations contribute to the risk of ***:Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1,a multistage association study was conducted to identify EBV variations associated with NPC risk.A protein degradation assay was performed to characterize the functional relevance of the RPMS1 ***:Based on EBV-encoded RPMS1 variations,a single nucleotide polymorphism(SNP) in the EBV genome(locus 155391:G>A,named Gl 55391 A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China[P < 0.001,odds ratio(OR) = 4.47,95%confidence interval(CI) 2.71-7.37].The results were further validated in three independent cohorts from the NPC endemic region(P < 0.001,OR = 5.20,95%CI3.18-8.50 in 168 cases vs.241 controls,and P < 0.001,OR = 5.27,95%CI 4.06-6.85 in 726 cases vs.880 controls) and a non-endemic region(P < 0.001,OR = 7.52,95%CI 3.69-15.32 in 58 cases vs.612 controls).The combined analysis in 1109 cases and 2052 controls revealed that the SNP Gl 55391 A was strongly associated with NPC(P< 0.001,OR = 5.27,95%CI 4.31-6.44).Moreover,the frequency of the SNP Gl 55391 A was associated with NPC incidence but was not associated with the incidences of other EBV-related ***,the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 ***:Our study identified an EBV variation specifically and significantly associated with a high risk of *** findings provide insights into the pathogenesis of NPC and strategies for prevention.

关键词： Epstein-Barr virus Nasopharyngeal carcinoma RPMS1 Association

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Biliary tract cancer stem cells-translational options and challenges

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World Journal of Gastroenterology 2017年第14期23卷 2470-2482页

作者： Christian Mayr Matthias Ocker Markus Ritter Martin Pichler Daniel Neureiter Tobias Kiesslich department of Internal Medicine I Paracelsus Medical University Laboratory for Tumour biology and experimental Therapies Institute of Physiology and PathophysiologyParacelsus Medical University Tanslational Medicine oncology department of Gastroenterology CBF CharitéUniversity Medicine Berlin Laboratory for Tumour biology and experimental Therapies(TREAT) Laboratory for Functional and Molecular Membrane PhysiologyParacelsus Medical University department for Radon therapy Research Ludwig Boltzmann Cluster for Arthritis and RehabilitationInstitute of Physiology and PathophysiologyParacelsus Medical University Research Unit for Non-coding RNA and genome editing in cancer Division of OncologyDepartment of Internal MedicineMedical University of Graz Institute of Pathology Paracelsus Medical University Cancer Cluster Salzburg

Management of biliary tract cancer remains challenging. tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.

关键词： Biliary tract cancer cancer stem cells Cancer stem cell markers tumor microenvironment Micro-RNAs

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