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Molecular Pharmacology

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Research ArticleArticle

A Novel β-Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage

David M. Smith, Aslamuzzaman Kazi, Lisa Smith, Timothy E. Long, Bart Heldreth, Edward Turos and Q. Ping Dou
Molecular Pharmacology June 2002, 61 (6) 1348-1358; DOI: https://doi.org/10.1124/mol.61.6.1348
David M. Smith
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Aslamuzzaman Kazi
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Lisa Smith
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Timothy E. Long
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Bart Heldreth
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Edward Turos
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Q. Ping Dou
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Abstract

Many of the anticancer drugs in current use are toxic and thus limited in their efficacy. It therefore becomes essential to develop novel chemotherapeutic agents with lower levels of toxicity. The β-lactam antibiotics have been used for many years to treat bacterial infections with limited or no toxicity. Until now, it has never been shown that β-lactams could kill tumor cells. Here, for the first time, we have discovered and characterized the apoptosis-inducing properties of a family of novel β-lactam antibiotics against human leukemia, breast, prostate, and head-and-neck cancer cells. We found that one particular lead compound (lactam 1) with anN-methylthio group was able to induce DNA damage and inhibit DNA replication in Jurkat T cells within a 2-h treatment. This was followed by p38 mitogen-activated protein kinase activation, S phase arrest, and apoptotic cell death. p38 was found to be a central player in β-lactam-induced apoptosis and resided downstream of DNA damage but upstream of caspase activation. Accompanying caspase-8 activation was cleavage of the pro-apoptotic Bcl-2 family protein Bid, and release of the mitochondrial cytochrome c. This was also associated with activation of caspase-9 and -3. Analogs of lactam 1 in which the N-methylthio group was replaced with other organothio chains exhibited progressive decreased potencies to induce DNA damage, p38 kinase activation, S phase arrest, and apoptosis, demonstrating requirement of the N-methylthio group. Because of the ease of synthesis and structural manipulation, we believe these β-lactams may have the potential to be developed into anticancer agents.

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Molecular Pharmacology: 61 (6)
Molecular Pharmacology
Vol. 61, Issue 6
1 Jun 2002
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Research ArticleArticle

A Novel β-Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage

David M. Smith, Aslamuzzaman Kazi, Lisa Smith, Timothy E. Long, Bart Heldreth, Edward Turos and Q. Ping Dou
Molecular Pharmacology June 1, 2002, 61 (6) 1348-1358; DOI: https://doi.org/10.1124/mol.61.6.1348

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Research ArticleArticle

A Novel β-Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage

David M. Smith, Aslamuzzaman Kazi, Lisa Smith, Timothy E. Long, Bart Heldreth, Edward Turos and Q. Ping Dou
Molecular Pharmacology June 1, 2002, 61 (6) 1348-1358; DOI: https://doi.org/10.1124/mol.61.6.1348
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