A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage.
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 beta-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 beta-lactams could kill tumor cells. Here, for the first time, we have discovered and characterized the apoptosis-inducing properties of a family of novel beta-lactam antibiotics against human leukemia, breast, prostate, and head-and-neck cancer cells. We found that one particular lead compound (lactam 1) with an N-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 beta-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 beta-lactams may have the potential to be developed into anticancer agents.
Smith
David M
DM
Drug Discovery Program, and the Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, Florida 33612-9497, USA.
Kazi
Aslamuzzaman
A
Smith
Lisa
L
Long
Timothy E
TE
Heldreth
Bart
B
Turos
Edward
E
Dou
Q Ping
QP
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects; D047090:beta-Lactams; D048051:p38 Mitogen-Activated Protein Kinases
D000900:Anti-Bacterial Agents; D003574:Cytochrome c Group; D047090:beta-Lactams; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases