Novel N-thiolated beta-lactam antibiotics selectively induce apoptosis in human tumor and transformed, but not normal or nontransformed, cells.
Historically, it has been shown that the beta-lactam antibiotics play an essential role in treating bacterial infections while demonstrating selectivity for prokaryotic cells. We recently reported that certain N-methylthio-substituted beta-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 beta-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 beta-lactams into novel anticancer agents.
Kazi
Aslamuzzaman
A
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Hill
Randy
R
Long
Timothy E
TE
Kuhn
Deborah J
DJ
Turos
Edward
E
Dou
Q Ping
QP
D017209:Apoptosis; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000187:drug effects*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
D047090:beta-Lactams