Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway
Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the maj...
Gespeichert in:
| Veröffentlicht in: | Apoptosis (London) 2019-06, Vol.24 (5-6), p.414-433 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 433 |
|---|---|
| container_issue | 5-6 |
| container_start_page | 414 |
| container_title | Apoptosis (London) |
| container_volume | 24 |
| creator | Datta, Satabdi Choudhury, Diptiman Das, Amlan Mukherjee, Dipanwita Das Dasgupta, Moumita Bandopadhyay, Shreya Chakrabarti, Gopal |
| description | Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity. ROS here played a crucial role in modulating Akt activity when autophagy process was hindered by chloroquine, excessive ROS accumulation in the cell inhibited Akt activity. In addition, chloroquine pre-treatment followed by taxol (10 nM) treatment did not show significant toxicity towards non-carcinomas WI38 cells (lung fibroblast cells). Thus autophagy inhibition by CQ pre-treatment can be used as a fruitful strategy to combat the phenomenon of paclitaxel resistance development as well as metastasis in lung cancer. |
| doi_str_mv | 10.1007/s10495-019-01526-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2180264809</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2180264809</sourcerecordid><originalsourceid>FETCH-LOGICAL-c290y-fdb152cdd30787649db53d61d3a800fc4bd73b66f46c7108ec84d66638aca45d3</originalsourceid><addsrcrecordid>eNp9kUFu1TAQhiMEoqVwARbIEutQO04cZ_lUQUGqVKmAxC6a2M6LK8cOttOSa_UYLDgT074COxaWrZl_vhnPXxSvGX3HKG1PE6N115SUdXiaSpTbk-KYNS0vRdt8e4pvLmgpmWyOihcpXVNKueT18-KI01a0VLbHxc_dmsMywX4j1k92sNkGT25tnoiaXIjh-2q9IdHcmJgTWUA5m-GHcRhKNmXwyhDwmkDOxq-QTSKzyYCZbBVZAkazBYd0Mq0zeOKDTzM4R9zq9wS08UFBVNaHGciuqTuijHOJ3FggV5efkaYtYjWZg14dPMwXRvLrrlQY9shdIE-3sL0sno3gknn1eJ8UXz-8_3L2sby4PP90trsoVdXRrRz1gMtSWuMSZCvqTg8N14JpDpLSUdWDbvkgxFgL1TIqjZK1FkJwCQrqRvOT4u2Bu9xvx6TcX4c1emzZV0zSStSSdqiqDioVQ0rRjP0S7Qxx6xnt7-3rD_b1aF__YF-_YdGbR_Q64L__lvzxCwX8IEiY8nsT__X-D_Y3qLGtBA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2180264809</pqid></control><display><type>article</type><title>Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway</title><source>MEDLINE</source><source>SpringerNature Journals</source><creator>Datta, Satabdi ; Choudhury, Diptiman ; Das, Amlan ; Mukherjee, Dipanwita Das ; Dasgupta, Moumita ; Bandopadhyay, Shreya ; Chakrabarti, Gopal</creator><creatorcontrib>Datta, Satabdi ; Choudhury, Diptiman ; Das, Amlan ; Mukherjee, Dipanwita Das ; Dasgupta, Moumita ; Bandopadhyay, Shreya ; Chakrabarti, Gopal</creatorcontrib><description>Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity. ROS here played a crucial role in modulating Akt activity when autophagy process was hindered by chloroquine, excessive ROS accumulation in the cell inhibited Akt activity. In addition, chloroquine pre-treatment followed by taxol (10 nM) treatment did not show significant toxicity towards non-carcinomas WI38 cells (lung fibroblast cells). Thus autophagy inhibition by CQ pre-treatment can be used as a fruitful strategy to combat the phenomenon of paclitaxel resistance development as well as metastasis in lung cancer.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-019-01526-y</identifier><identifier>PMID: 30767087</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>A549 Cells ; Adenocarcinoma ; AKT protein ; Antineoplastic Agents, Phytogenic - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; beta Catenin - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cancer Research ; Cell Biology ; Cell Cycle Checkpoints - drug effects ; Cell Line ; Cell Survival - drug effects ; Chemoresistance ; Chemotherapy ; Chloroquine ; Chloroquine - pharmacology ; Damage accumulation ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm - drug effects ; Efflux ; G1 phase ; Humans ; Lung cancer ; Lung carcinoma ; Mesenchyme ; Metastases ; Metastasis ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - metabolism ; Modulation ; Mutation ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - pathology ; Non-small cell lung carcinoma ; Oncology ; Paclitaxel ; Paclitaxel - pharmacology ; Phagocytosis ; Pretreatment ; Proto-Oncogene Proteins c-akt - metabolism ; Reactive Oxygen Species - metabolism ; Signal transduction ; Stem cells ; Superoxide ; Taxol ; Toxicity ; Tubulin ; Virology ; Wnt protein ; Wnt Signaling Pathway - drug effects ; β-Catenin</subject><ispartof>Apoptosis (London), 2019-06, Vol.24 (5-6), p.414-433</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2019</rights><rights>Apoptosis is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c290y-fdb152cdd30787649db53d61d3a800fc4bd73b66f46c7108ec84d66638aca45d3</citedby><cites>FETCH-LOGICAL-c290y-fdb152cdd30787649db53d61d3a800fc4bd73b66f46c7108ec84d66638aca45d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-019-01526-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-019-01526-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30767087$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Datta, Satabdi</creatorcontrib><creatorcontrib>Choudhury, Diptiman</creatorcontrib><creatorcontrib>Das, Amlan</creatorcontrib><creatorcontrib>Mukherjee, Dipanwita Das</creatorcontrib><creatorcontrib>Dasgupta, Moumita</creatorcontrib><creatorcontrib>Bandopadhyay, Shreya</creatorcontrib><creatorcontrib>Chakrabarti, Gopal</creatorcontrib><title>Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity. ROS here played a crucial role in modulating Akt activity when autophagy process was hindered by chloroquine, excessive ROS accumulation in the cell inhibited Akt activity. In addition, chloroquine pre-treatment followed by taxol (10 nM) treatment did not show significant toxicity towards non-carcinomas WI38 cells (lung fibroblast cells). Thus autophagy inhibition by CQ pre-treatment can be used as a fruitful strategy to combat the phenomenon of paclitaxel resistance development as well as metastasis in lung cancer.</description><subject>A549 Cells</subject><subject>Adenocarcinoma</subject><subject>AKT protein</subject><subject>Antineoplastic Agents, Phytogenic - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>beta Catenin - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Chloroquine</subject><subject>Chloroquine - pharmacology</subject><subject>Damage accumulation</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Efflux</subject><subject>G1 phase</subject><subject>Humans</subject><subject>Lung cancer</subject><subject>Lung carcinoma</subject><subject>Mesenchyme</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Modulation</subject><subject>Mutation</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Non-small cell lung carcinoma</subject><subject>Oncology</subject><subject>Paclitaxel</subject><subject>Paclitaxel - pharmacology</subject><subject>Phagocytosis</subject><subject>Pretreatment</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Signal transduction</subject><subject>Stem cells</subject><subject>Superoxide</subject><subject>Taxol</subject><subject>Toxicity</subject><subject>Tubulin</subject><subject>Virology</subject><subject>Wnt protein</subject><subject>Wnt Signaling Pathway - drug effects</subject><subject>β-Catenin</subject><issn>1360-8185</issn><issn>1573-675X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kUFu1TAQhiMEoqVwARbIEutQO04cZ_lUQUGqVKmAxC6a2M6LK8cOttOSa_UYLDgT074COxaWrZl_vhnPXxSvGX3HKG1PE6N115SUdXiaSpTbk-KYNS0vRdt8e4pvLmgpmWyOihcpXVNKueT18-KI01a0VLbHxc_dmsMywX4j1k92sNkGT25tnoiaXIjh-2q9IdHcmJgTWUA5m-GHcRhKNmXwyhDwmkDOxq-QTSKzyYCZbBVZAkazBYd0Mq0zeOKDTzM4R9zq9wS08UFBVNaHGciuqTuijHOJ3FggV5efkaYtYjWZg14dPMwXRvLrrlQY9shdIE-3sL0sno3gknn1eJ8UXz-8_3L2sby4PP90trsoVdXRrRz1gMtSWuMSZCvqTg8N14JpDpLSUdWDbvkgxFgL1TIqjZK1FkJwCQrqRvOT4u2Bu9xvx6TcX4c1emzZV0zSStSSdqiqDioVQ0rRjP0S7Qxx6xnt7-3rD_b1aF__YF-_YdGbR_Q64L__lvzxCwX8IEiY8nsT__X-D_Y3qLGtBA</recordid><startdate>201906</startdate><enddate>201906</enddate><creator>Datta, Satabdi</creator><creator>Choudhury, Diptiman</creator><creator>Das, Amlan</creator><creator>Mukherjee, Dipanwita Das</creator><creator>Dasgupta, Moumita</creator><creator>Bandopadhyay, Shreya</creator><creator>Chakrabarti, Gopal</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7RQ</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>U9A</scope></search><sort><creationdate>201906</creationdate><title>Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway</title><author>Datta, Satabdi ; Choudhury, Diptiman ; Das, Amlan ; Mukherjee, Dipanwita Das ; Dasgupta, Moumita ; Bandopadhyay, Shreya ; Chakrabarti, Gopal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c290y-fdb152cdd30787649db53d61d3a800fc4bd73b66f46c7108ec84d66638aca45d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>A549 Cells</topic><topic>Adenocarcinoma</topic><topic>AKT protein</topic><topic>Antineoplastic Agents, Phytogenic - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>beta Catenin - metabolism</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Cell Biology</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>Chloroquine</topic><topic>Chloroquine - pharmacology</topic><topic>Damage accumulation</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Efflux</topic><topic>G1 phase</topic><topic>Humans</topic><topic>Lung cancer</topic><topic>Lung carcinoma</topic><topic>Mesenchyme</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mitochondria</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Modulation</topic><topic>Mutation</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Non-small cell lung carcinoma</topic><topic>Oncology</topic><topic>Paclitaxel</topic><topic>Paclitaxel - pharmacology</topic><topic>Phagocytosis</topic><topic>Pretreatment</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Signal transduction</topic><topic>Stem cells</topic><topic>Superoxide</topic><topic>Taxol</topic><topic>Toxicity</topic><topic>Tubulin</topic><topic>Virology</topic><topic>Wnt protein</topic><topic>Wnt Signaling Pathway - drug effects</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Datta, Satabdi</creatorcontrib><creatorcontrib>Choudhury, Diptiman</creatorcontrib><creatorcontrib>Das, Amlan</creatorcontrib><creatorcontrib>Mukherjee, Dipanwita Das</creatorcontrib><creatorcontrib>Dasgupta, Moumita</creatorcontrib><creatorcontrib>Bandopadhyay, Shreya</creatorcontrib><creatorcontrib>Chakrabarti, Gopal</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Career & Technical Education Database</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Apoptosis (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Datta, Satabdi</au><au>Choudhury, Diptiman</au><au>Das, Amlan</au><au>Mukherjee, Dipanwita Das</au><au>Dasgupta, Moumita</au><au>Bandopadhyay, Shreya</au><au>Chakrabarti, Gopal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway</atitle><jtitle>Apoptosis (London)</jtitle><stitle>Apoptosis</stitle><addtitle>Apoptosis</addtitle><date>2019-06</date><risdate>2019</risdate><volume>24</volume><issue>5-6</issue><spage>414</spage><epage>433</epage><pages>414-433</pages><issn>1360-8185</issn><eissn>1573-675X</eissn><abstract>Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity. ROS here played a crucial role in modulating Akt activity when autophagy process was hindered by chloroquine, excessive ROS accumulation in the cell inhibited Akt activity. In addition, chloroquine pre-treatment followed by taxol (10 nM) treatment did not show significant toxicity towards non-carcinomas WI38 cells (lung fibroblast cells). Thus autophagy inhibition by CQ pre-treatment can be used as a fruitful strategy to combat the phenomenon of paclitaxel resistance development as well as metastasis in lung cancer.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>30767087</pmid><doi>10.1007/s10495-019-01526-y</doi><tpages>20</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1360-8185 |
| ispartof | Apoptosis (London), 2019-06, Vol.24 (5-6), p.414-433 |
| issn | 1360-8185 1573-675X |
| language | eng |
| recordid | cdi_proquest_journals_2180264809 |
| source | MEDLINE; SpringerNature Journals |
| subjects | A549 Cells Adenocarcinoma AKT protein Antineoplastic Agents, Phytogenic - pharmacology Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects beta Catenin - metabolism Biochemistry Biomedical and Life Sciences Biomedicine Cancer Cancer Research Cell Biology Cell Cycle Checkpoints - drug effects Cell Line Cell Survival - drug effects Chemoresistance Chemotherapy Chloroquine Chloroquine - pharmacology Damage accumulation Dose-Response Relationship, Drug Drug Resistance, Neoplasm - drug effects Efflux G1 phase Humans Lung cancer Lung carcinoma Mesenchyme Metastases Metastasis Mitochondria Mitochondria - drug effects Mitochondria - metabolism Modulation Mutation Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - pathology Non-small cell lung carcinoma Oncology Paclitaxel Paclitaxel - pharmacology Phagocytosis Pretreatment Proto-Oncogene Proteins c-akt - metabolism Reactive Oxygen Species - metabolism Signal transduction Stem cells Superoxide Taxol Toxicity Tubulin Virology Wnt protein Wnt Signaling Pathway - drug effects β-Catenin |
| title | Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T14%3A25%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Autophagy%20inhibition%20with%20chloroquine%20reverts%20paclitaxel%20resistance%20and%20attenuates%20metastatic%20potential%20in%20human%20nonsmall%20lung%20adenocarcinoma%20A549%20cells%20via%20ROS%20mediated%20modulation%20of%20%CE%B2-catenin%20pathway&rft.jtitle=Apoptosis%20(London)&rft.au=Datta,%20Satabdi&rft.date=2019-06&rft.volume=24&rft.issue=5-6&rft.spage=414&rft.epage=433&rft.pages=414-433&rft.issn=1360-8185&rft.eissn=1573-675X&rft_id=info:doi/10.1007/s10495-019-01526-y&rft_dat=%3Cproquest_cross%3E2180264809%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2180264809&rft_id=info:pmid/30767087&rfr_iscdi=true |