Novel N-thiolated β-lactam antibiotics selectively induce apoptosis in human tumor and transformed, but not normal or nontransformed, cells
Identifieur interne : 005A99 ( Main/Exploration ); précédent : 005A98; suivant : 005B00Novel N-thiolated β-lactam antibiotics selectively induce apoptosis in human tumor and transformed, but not normal or nontransformed, cells
Auteurs : Aslamuzzaman Kazi [États-Unis] ; Randy Hill [États-Unis] ; Timothy E. Long [États-Unis] ; Deborah J. Kuhn [États-Unis] ; Edward Turos [États-Unis] ; Q. Ping Dou [États-Unis]Source :
- Biochemical pharmacology [ 0006-2952 ] ; 2004.
Descripteurs français
- KwdFr :
- MESH :
- anatomopathologie : Tumeurs de la prostate.
- pharmacologie : bêta-Lactames.
- Pascal (Inist)
- Apoptose, Cellules Jurkat, Cellules cancéreuses en culture, Cellules tueuses naturelles, Fibroblastes, Humains, Lignée de cellules transformées, Mâle, Transformation cellulaire virale, bêta-Lactames, β-Lactamines, DNA, Biochimie, Biologie moléculaire, Biophysique, Antibiotique, Apoptose, Mort cellulaire, Homme, Tumeur maligne, Normal, Cellule, Lésion, Anticancéreux, Médicament.
- Wicri :
- topic : Biochimie, Antibiotique, Homme, Médicament.
English descriptors
- KwdEn :
- Antibiotic, Antineoplastic agent, Apoptosis, Biochemistry, Biophysics, Cell, Cell Line, Transformed, Cell Transformation, Viral, Cell death, DNA, Drug, Fibroblasts (drug effects), Human, Humans, Jurkat Cells, Killer Cells, Natural (drug effects), Lesion, Male, Malignant tumor, Molecular biology, Normal, Prostatic Neoplasms (pathology), Tumor Cells, Cultured (drug effects), beta-Lactams (chemistry), beta-Lactams (pharmacology), β-Lactams.
- MESH :
- chemical , chemistry : beta-Lactams.
- drug effects : Fibroblasts, Killer Cells, Natural, Tumor Cells, Cultured.
- pathology : Prostatic Neoplasms.
- chemical , pharmacology : beta-Lactams.
- Apoptosis, Cell Line, Transformed, Cell Transformation, Viral, Humans, Jurkat Cells, Male.
Abstract
Historically, it has been shown that the p-lactam antibiotics play an essential role in treating bacterial infections while demonstrating selectivity for prokaryotic cells. We recently reported that certain N-methylthio-substituted β-lactam antibiotics had DNA-damaging and apoptosis-inducing activities in various tumor cells. However, whether these compounds affect human normal or nontransformed cells was unknown. In the current study, we first show that a lead compound (lactam 1) selectively induces apoptosis in human leukemic Jurkat T, but not in the nontransformed, immortalized human natural killer (NK) cells. Additionally, we screened a library of other N-methylthiolated β-lactams to determine their structure-activity relationships (SARs), and found lactam 12 to have the highest apoptosis-inducing activity against human leukemic Jurkat T cells, associated with increased DNA-damaging potency. Furthermore, we demonstrate that lactam 12, as well as lactam 1, potently inhibits colony formation of human prostate cancer cells. We also show that lactam 12 induces apoptosis in human breast, prostate, and head-and-neck cancer cells. Finally, lactam 12 induces apoptosis selectively in Jurkat T and simian virus 40-transformed, but not in nontransformed NK and parental normal fibroblast, cells. Our results suggest that there is potential for developing this class of β-lactams into novel anticancer agents.
Affiliations:
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Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Hill, Randy" sort="Hill, Randy" uniqKey="Hill R" first="Randy" last="Hill">Randy Hill</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Long, Timothy E" sort="Long, Timothy E" uniqKey="Long T" first="Timothy E." last="Long">Timothy E. Long</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Chemistry, College of Arts and Sciences, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Kuhn, Deborah J" sort="Kuhn, Deborah J" uniqKey="Kuhn D" first="Deborah J." last="Kuhn">Deborah J. Kuhn</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Turos, Edward" sort="Turos, Edward" uniqKey="Turos E" first="Edward" last="Turos">Edward Turos</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Chemistry, College of Arts and Sciences, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author><author><name sortKey="Ping Dou, Q" sort="Ping Dou, Q" uniqKey="Ping Dou Q" first="Q." last="Ping Dou">Q. Ping Dou</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida</s1><s2>Tampa, FL 33612</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Floride</region><settlement type="city">Tampa</settlement></placeName><orgName type="university">Université de Floride du Sud</orgName></affiliation></author></analytic><series><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antibiotic</term><term>Antineoplastic agent</term><term>Apoptosis</term><term>Biochemistry</term><term>Biophysics</term><term>Cell</term><term>Cell Line, Transformed</term><term>Cell Transformation, Viral</term><term>Cell death</term><term>DNA</term><term>Drug</term><term>Fibroblasts (drug effects)</term><term>Human</term><term>Humans</term><term>Jurkat Cells</term><term>Killer Cells, Natural (drug effects)</term><term>Lesion</term><term>Male</term><term>Malignant tumor</term><term>Molecular biology</term><term>Normal</term><term>Prostatic Neoplasms (pathology)</term><term>Tumor Cells, Cultured (drug effects)</term><term>beta-Lactams (chemistry)</term><term>beta-Lactams (pharmacology)</term><term>β-Lactams</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Apoptose</term><term>Cellules Jurkat</term><term>Cellules cancéreuses en culture ()</term><term>Cellules tueuses naturelles ()</term><term>Fibroblastes ()</term><term>Humains</term><term>Lignée de cellules transformées</term><term>Mâle</term><term>Transformation cellulaire virale</term><term>Tumeurs de la prostate (anatomopathologie)</term><term>bêta-Lactames ()</term><term>bêta-Lactames (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>beta-Lactams</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Tumeurs de la prostate</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Fibroblasts</term><term>Killer Cells, Natural</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Prostatic Neoplasms</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>bêta-Lactames</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>beta-Lactams</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Apoptosis</term><term>Cell Line, Transformed</term><term>Cell Transformation, Viral</term><term>Humans</term><term>Jurkat Cells</term><term>Male</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Apoptose</term><term>Cellules Jurkat</term><term>Cellules cancéreuses en culture</term><term>Cellules tueuses naturelles</term><term>Fibroblastes</term><term>Humains</term><term>Lignée de cellules transformées</term><term>Mâle</term><term>Transformation cellulaire virale</term><term>bêta-Lactames</term><term>β-Lactamines</term><term>DNA</term><term>Biochimie</term><term>Biologie moléculaire</term><term>Biophysique</term><term>Antibiotique</term><term>Apoptose</term><term>Mort cellulaire</term><term>Homme</term><term>Tumeur maligne</term><term>Normal</term><term>Cellule</term><term>Lésion</term><term>Anticancéreux</term><term>Médicament</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Biochimie</term><term>Antibiotique</term><term>Homme</term><term>Médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Historically, it has been shown that the p-lactam antibiotics play an essential role in treating bacterial infections while demonstrating selectivity for prokaryotic cells. We recently reported that certain N-methylthio-substituted β-lactam antibiotics had DNA-damaging and apoptosis-inducing activities in various tumor cells. However, whether these compounds affect human normal or nontransformed cells was unknown. In the current study, we first show that a lead compound (lactam 1) selectively induces apoptosis in human leukemic Jurkat T, but not in the nontransformed, immortalized human natural killer (NK) cells. Additionally, we screened a library of other N-methylthiolated β-lactams to determine their structure-activity relationships (SARs), and found lactam 12 to have the highest apoptosis-inducing activity against human leukemic Jurkat T cells, associated with increased DNA-damaging potency. Furthermore, we demonstrate that lactam 12, as well as lactam 1, potently inhibits colony formation of human prostate cancer cells. We also show that lactam 12 induces apoptosis in human breast, prostate, and head-and-neck cancer cells. Finally, lactam 12 induces apoptosis selectively in Jurkat T and simian virus 40-transformed, but not in nontransformed NK and parental normal fibroblast, cells. Our results suggest that there is potential for developing this class of β-lactams into novel anticancer agents.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Floride</li></region><settlement><li>Tampa</li></settlement><orgName><li>Université de Floride du Sud</li></orgName></list><tree><country name="États-Unis"><region name="Floride"><name sortKey="Kazi, Aslamuzzaman" sort="Kazi, Aslamuzzaman" uniqKey="Kazi A" first="Aslamuzzaman" last="Kazi">Aslamuzzaman Kazi</name></region><name sortKey="Hill, Randy" sort="Hill, Randy" uniqKey="Hill R" first="Randy" last="Hill">Randy Hill</name><name sortKey="Kuhn, Deborah J" sort="Kuhn, Deborah J" uniqKey="Kuhn D" first="Deborah J." last="Kuhn">Deborah J. Kuhn</name><name sortKey="Long, Timothy E" sort="Long, Timothy E" uniqKey="Long T" first="Timothy E." last="Long">Timothy E. Long</name><name sortKey="Ping Dou, Q" sort="Ping Dou, Q" uniqKey="Ping Dou Q" first="Q." last="Ping Dou">Q. Ping Dou</name><name sortKey="Turos, Edward" sort="Turos, Edward" uniqKey="Turos E" first="Edward" last="Turos">Edward Turos</name><name sortKey="Turos, Edward" sort="Turos, Edward" uniqKey="Turos E" first="Edward" last="Turos">Edward Turos</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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