Effect of dual inhibition of apoptosis and autophagy in prostate cancer
Identifieur interne : 001401 ( Main/Exploration ); précédent : 001400; suivant : 001402Effect of dual inhibition of apoptosis and autophagy in prostate cancer
Auteurs : Ahamed Saleem [États-Unis, Arabie saoudite] ; Dmitri Dvorzhinski [États-Unis] ; Urmila Santanam [États-Unis] ; Robin Mathew [États-Unis] ; Kevin Bray [États-Unis] ; Mark Stein [États-Unis] ; Eileen White [États-Unis] ; Robert S. Dipaola [États-Unis]Source :
- The Prostate [ 0270-4137 ] ; 2012-09-01.
English descriptors
- Teeft :
- Apoptosis, Assay, Autophagic, Autophagic clearance, Autophagy, Autophagy induction, Autophagy inhibition, Autophagy modulation, Autophagy pathway, Autophagy regulator beclin1, Beclin1, Beclin1 sirna, Cancer cells, Cell survival, Cell viability, Cell viability assay, Cells transfected, Clin cancer, Combination therapy, Conductedin triplicate, Current study, Cytotoxic effect, Cytotoxicity, Dichlorodihydrofluorescene diacetate, Dipaola, Drug development, Drug resistance, Dual apoptotic, Dual inhibition, Dysfunctional, Dysfunctional mitochondria, Flow cytometry, Fluorescence microscopy, Future studies, Gleason score, Goat serum, Grade tumors, Human androgen, Human tissue, Lamin sirna, Lncap, Lncap cells, Mcherryparkin reporter, Metabolic stress, Mitochondrial function, Mitochondrion, Mouse model, Other groups, Primary antibody, Prostate, Prostate cancer, Prostate cancer cell line, Prostate cancer cells, Recent studies, Resistance mechanism, Results support, Sirna, Therapeutic effectiveness, Therapeutic inhibition, Treatment group, Tumor growth, Tumor xenografts, Untreated control, Vehicle control, Xenograft.
Abstract
PURPOSE: Targeting multiple anti‐apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT‐737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti‐malarial drug that inhibits autophagy, will increase cytotoxicity of ABT‐737. EXPERIMENTAL DESIGN: Cytotoxicity of ABT‐737 and HCQ was assessed in vitro in PC‐3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry‐Parkin reporter. RESULTS: Induction of autophagy by ABT‐737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT‐737 both in vitro and in vivo. ABT‐737 induced LC‐3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT‐737 and HCQ was a mechanism of cytotoxicity. CONCLUSIONS: We demonstrated that autophagy inhibition with HCQ enhances ABT‐737 cytotoxicity in vitro and in vivo, that LC‐3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies. Prostate 72:1374–1381, 2012. © 2012 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/pros.22487
Affiliations:
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Dipaola</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>The Cancer Institute of New Jersey, New Brunswick</wicri:cityArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick</wicri:cityArea></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Jersey</region></placeName><wicri:cityArea>Correspondence address: 195 Little Albany Street, Room 2044, New Brunswick</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Prostate</title><title level="j" type="alt">PROSTATE, THE</title><idno type="ISSN">0270-4137</idno><idno type="eISSN">1097-0045</idno><imprint><biblScope unit="vol">72</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1374">1374</biblScope><biblScope unit="page" to="1381">1381</biblScope><biblScope unit="page-count">8</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-09-01">2012-09-01</date></imprint><idno type="ISSN">0270-4137</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0270-4137</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Apoptosis</term><term>Assay</term><term>Autophagic</term><term>Autophagic clearance</term><term>Autophagy</term><term>Autophagy induction</term><term>Autophagy inhibition</term><term>Autophagy modulation</term><term>Autophagy pathway</term><term>Autophagy regulator beclin1</term><term>Beclin1</term><term>Beclin1 sirna</term><term>Cancer cells</term><term>Cell survival</term><term>Cell viability</term><term>Cell viability assay</term><term>Cells transfected</term><term>Clin cancer</term><term>Combination therapy</term><term>Conductedin triplicate</term><term>Current study</term><term>Cytotoxic effect</term><term>Cytotoxicity</term><term>Dichlorodihydrofluorescene diacetate</term><term>Dipaola</term><term>Drug development</term><term>Drug resistance</term><term>Dual apoptotic</term><term>Dual inhibition</term><term>Dysfunctional</term><term>Dysfunctional mitochondria</term><term>Flow cytometry</term><term>Fluorescence microscopy</term><term>Future studies</term><term>Gleason score</term><term>Goat serum</term><term>Grade tumors</term><term>Human androgen</term><term>Human tissue</term><term>Lamin sirna</term><term>Lncap</term><term>Lncap cells</term><term>Mcherryparkin reporter</term><term>Metabolic stress</term><term>Mitochondrial function</term><term>Mitochondrion</term><term>Mouse model</term><term>Other groups</term><term>Primary antibody</term><term>Prostate</term><term>Prostate cancer</term><term>Prostate cancer cell line</term><term>Prostate cancer cells</term><term>Recent studies</term><term>Resistance mechanism</term><term>Results support</term><term>Sirna</term><term>Therapeutic effectiveness</term><term>Therapeutic inhibition</term><term>Treatment group</term><term>Tumor growth</term><term>Tumor xenografts</term><term>Untreated control</term><term>Vehicle control</term><term>Xenograft</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">PURPOSE: Targeting multiple anti‐apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as ABT‐737. Given recent studies demonstrating that autophagy is a resistance mechanism to multiple therapeutic agents in the setting of apoptotic inhibition, we hypothesized that hydroxychloroquine (HCQ), an anti‐malarial drug that inhibits autophagy, will increase cytotoxicity of ABT‐737. EXPERIMENTAL DESIGN: Cytotoxicity of ABT‐737 and HCQ was assessed in vitro in PC‐3 and LNCaP cells, and in vivo in a xenograft mouse model. The role of autophagy as a resistance mechanism was assessed by siRNA knockdown of the essential autophagy gene beclin1. ROS was measured by flow cytometry, and mitophagy assessed by the mCherry‐Parkin reporter. RESULTS: Induction of autophagy by ABT‐737 was a mechanism of resistance in prostate cancer cell lines. Therapeutic inhibition of autophagy with HCQ increased cytotoxicity of ABT‐737 both in vitro and in vivo. ABT‐737 induced LC‐3 and decreased p62 expression by immunoblot in cell lines and by immunohistochemistry in tumors in vivo. Assessment of ROS and mitochondria demonstrated that ROS production by ABT‐737 and HCQ was a mechanism of cytotoxicity. CONCLUSIONS: We demonstrated that autophagy inhibition with HCQ enhances ABT‐737 cytotoxicity in vitro and in vivo, that LC‐3 and p62 represent assessable markers in human tissue for future clinical trials, and that ROS induction is a mechanism of cytotoxicity. These results support a new paradigm of dual targeting of apoptosis and autophagy in future clinical studies. Prostate 72:1374–1381, 2012. © 2012 Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>Arabie saoudite</li><li>États-Unis</li></country><region><li>New Jersey</li></region></list><tree><country name="États-Unis"><region name="New Jersey"><name sortKey="Saleem, Ahamed" sort="Saleem, Ahamed" uniqKey="Saleem A" first="Ahamed" last="Saleem">Ahamed Saleem</name></region><name sortKey="Bray, Kevin" sort="Bray, Kevin" uniqKey="Bray K" first="Kevin" last="Bray">Kevin Bray</name><name sortKey="Dipaola, Robert S" sort="Dipaola, Robert S" uniqKey="Dipaola R" first="Robert S." last="Dipaola">Robert S. Dipaola</name><name sortKey="Dipaola, Robert S" sort="Dipaola, Robert S" uniqKey="Dipaola R" first="Robert S." last="Dipaola">Robert S. Dipaola</name><name sortKey="Dipaola, Robert S" sort="Dipaola, Robert S" uniqKey="Dipaola R" first="Robert S." last="Dipaola">Robert S. Dipaola</name><name sortKey="Dipaola, Robert S" sort="Dipaola, Robert S" uniqKey="Dipaola R" first="Robert S." last="Dipaola">Robert S. Dipaola</name><name sortKey="Dvorzhinski, Dmitri" sort="Dvorzhinski, Dmitri" uniqKey="Dvorzhinski D" first="Dmitri" last="Dvorzhinski">Dmitri Dvorzhinski</name><name sortKey="Mathew, Robin" sort="Mathew, Robin" uniqKey="Mathew R" first="Robin" last="Mathew">Robin Mathew</name><name sortKey="Santanam, Urmila" sort="Santanam, Urmila" uniqKey="Santanam U" first="Urmila" last="Santanam">Urmila Santanam</name><name sortKey="Stein, Mark" sort="Stein, Mark" uniqKey="Stein M" first="Mark" last="Stein">Mark Stein</name><name sortKey="Stein, Mark" sort="Stein, Mark" uniqKey="Stein M" first="Mark" last="Stein">Mark Stein</name><name sortKey="White, Eileen" sort="White, Eileen" uniqKey="White E" first="Eileen" last="White">Eileen White</name><name sortKey="White, Eileen" sort="White, Eileen" uniqKey="White E" first="Eileen" last="White">Eileen White</name><name sortKey="White, Eileen" sort="White, Eileen" uniqKey="White E" first="Eileen" last="White">Eileen White</name></country><country name="Arabie saoudite"><noRegion><name sortKey="Saleem, Ahamed" sort="Saleem, Ahamed" uniqKey="Saleem A" first="Ahamed" last="Saleem">Ahamed Saleem</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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