Computational analysis of image‐based drug profiling predicts synergistic drug combinations: Applications in triple‐negative breast cancer
Identifieur interne : 001C02 ( Ncbi/Curation ); précédent : 001C01; suivant : 001C03Computational analysis of image‐based drug profiling predicts synergistic drug combinations: Applications in triple‐negative breast cancer
Auteurs : Miriam B. Brandl ; Eddy Pasquier ; Fuhai Li ; Dominik Beck ; Sufang Zhang ; Hong Zhao ; Maria Kavallaris ; Stephen T. C. WongSource :
- Molecular Oncology [ 1574-7891 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Apoptose (), Benzamides (usage thérapeutique), Femelle, Humains, Kinésine (antagonistes et inhibiteurs), Kinésine (métabolisme), Lignée cellulaire tumorale, Mitose (), Pyrimidines (usage thérapeutique), Quinazolines (usage thérapeutique), Souris, Souris de lignée BALB C, Synergie des médicaments, Tests d'activité antitumorale sur modèle de xénogreffe, Thiones (usage thérapeutique), Tumeurs du sein triple-négatives (métabolisme), Tumeurs du sein triple-négatives (traitement médicamenteux), Vinblastine (usage thérapeutique).
- MESH :
- antagonistes et inhibiteurs : Kinésine.
- métabolisme : Kinésine, Tumeurs du sein triple-négatives.
- traitement médicamenteux : Tumeurs du sein triple-négatives.
- usage thérapeutique : Benzamides, Pyrimidines, Quinazolines, Thiones, Vinblastine.
- Animaux, Apoptose, Femelle, Humains, Lignée cellulaire tumorale, Mitose, Souris, Souris de lignée BALB C, Synergie des médicaments, Tests d'activité antitumorale sur modèle de xénogreffe.
English descriptors
- KwdEn :
- Animals, Apoptosis (drug effects), Benzamides (therapeutic use), Cell Line, Tumor, Drug Synergism, Female, Humans, Kinesin (antagonists & inhibitors), Kinesin (metabolism), Mice, Mice, Inbred BALB C, Mitosis (drug effects), Pyrimidines (therapeutic use), Quinazolines (therapeutic use), Thiones (therapeutic use), Triple Negative Breast Neoplasms (drug therapy), Triple Negative Breast Neoplasms (metabolism), Vinblastine (therapeutic use), Xenograft Model Antitumor Assays.
- MESH :
- chemical , antagonists & inhibitors : Kinesin.
- chemical , metabolism : Kinesin.
- chemical , therapeutic use : Benzamides, Pyrimidines, Quinazolines, Thiones, Vinblastine.
- drug effects : Apoptosis, Mitosis.
- drug therapy : Triple Negative Breast Neoplasms.
- metabolism : Triple Negative Breast Neoplasms.
- Animals, Cell Line, Tumor, Drug Synergism, Female, Humans, Mice, Mice, Inbred BALB C, Xenograft Model Antitumor Assays.
Abstract
An imaged‐based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi‐drug therapies for the treatment of triple‐negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple‐negative breast cancer (TNBC) was achieved by integrating high‐content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA‐approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule‐targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib‐induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image‐based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard‐to‐treat cancers.
Url:
DOI: 10.1016/j.molonc.2014.06.007
PubMed: 24997502
PubMed Central: 4253311
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PMC:4253311Le document en format XML
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Wong</name><affiliation><nlm:aff id="mol22014881548-aff-0003"></nlm:aff></affiliation></author></analytic><series><title level="j">Molecular Oncology</title><idno type="ISSN">1574-7891</idno><idno type="eISSN">1878-0261</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apoptosis (drug effects)</term><term>Benzamides (therapeutic use)</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Kinesin (antagonists & inhibitors)</term><term>Kinesin (metabolism)</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mitosis (drug effects)</term><term>Pyrimidines (therapeutic use)</term><term>Quinazolines (therapeutic use)</term><term>Thiones (therapeutic use)</term><term>Triple Negative Breast Neoplasms (drug therapy)</term><term>Triple Negative Breast Neoplasms (metabolism)</term><term>Vinblastine (therapeutic use)</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Apoptose ()</term><term>Benzamides (usage thérapeutique)</term><term>Femelle</term><term>Humains</term><term>Kinésine (antagonistes et inhibiteurs)</term><term>Kinésine (métabolisme)</term><term>Lignée cellulaire tumorale</term><term>Mitose ()</term><term>Pyrimidines (usage thérapeutique)</term><term>Quinazolines (usage thérapeutique)</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Synergie des médicaments</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term><term>Thiones (usage thérapeutique)</term><term>Tumeurs du sein triple-négatives (métabolisme)</term><term>Tumeurs du sein triple-négatives (traitement médicamenteux)</term><term>Vinblastine (usage thérapeutique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Kinesin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Kinesin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Benzamides</term><term>Pyrimidines</term><term>Quinazolines</term><term>Thiones</term><term>Vinblastine</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Kinésine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Mitosis</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Triple Negative Breast Neoplasms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Triple Negative Breast Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Kinésine</term><term>Tumeurs du sein triple-négatives</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs du sein triple-négatives</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Benzamides</term><term>Pyrimidines</term><term>Quinazolines</term><term>Thiones</term><term>Vinblastine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Drug Synergism</term><term>Female</term><term>Humans</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Apoptose</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mitose</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Synergie des médicaments</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>An imaged‐based profiling and analysis system was developed to predict clinically effective synergistic drug combinations that could accelerate the identification of effective multi‐drug therapies for the treatment of triple‐negative breast cancer and other challenging malignancies. The identification of effective drug combinations for the treatment of triple‐negative breast cancer (TNBC) was achieved by integrating high‐content screening, computational analysis, and experimental biology. The approach was based on altered cellular phenotypes induced by 55 FDA‐approved drugs and biologically active compounds, acquired using fluorescence microscopy and retained in multivariate compound profiles. Dissimilarities between compound profiles guided the identification of 5 combinations, which were assessed for qualitative interaction on TNBC cell growth. The combination of the microtubule‐targeting drug vinblastine with KSP/Eg5 motor protein inhibitors monastrol or ispinesib showed potent synergism in 3 independent TNBC cell lines, which was not substantiated in normal fibroblasts. The synergistic interaction was mediated by an increase in mitotic arrest with cells demonstrating typical ispinesib‐induced monopolar mitotic spindles, which translated into enhanced apoptosis induction. The antitumour activity of the combination vinblastine/ispinesib was confirmed in an orthotopic mouse model of TNBC. Compared to single drug treatment, combination treatment significantly reduced tumour growth without causing increased toxicity. Image‐based profiling and analysis led to the rapid discovery of a drug combination effective against TNBC in vitro and in vivo, and has the potential to lead to the development of new therapeutic options in other hard‐to‐treat cancers.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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