Induction of tumor cell apoptosis by a novel class of N-thiolated beta-lactam antibiotics with structural modifications at N1 and C3 of the lactam ring.
The investigation of novel anti-tumor agents that preferentially select for malignant cells with a tolerable toxicity level has been the focus of anti-cancer drug discovery. Our laboratories have previously reported that certain N-alkylthiolated beta-lactams had DNA-damaging and apoptosis-inducing activity in various tumor lines but not in nontransformed cells. In the current study, we further delineated the effects of substitutions at C3 or N1 of the lactam ring for cell death-inducing capability with close attention paid to a discernible structure-activity relationship (SAR). We found that two beta-lactam analogs (JG-5 and JG-19), both containing a branched-chain moiety at C3 of the lactam ring, exhibit potent apoptosis-inducing activity. Additionally, JG-5 exhibited superior in vitro biological activity over JG-19 owing to structural modifications made to substituents at the N1 and C3 positions of the lactam ring. Furthermore, the branched beta-lactams were able to inhibit growth of mice bearing breast cancer xenografts, associated with induction of DNA damage and apoptosis in tumor tissues. Our results strongly warrant further investigation into these novel beta-lactams as potential anti-cancer therapeutics.
Frezza
Michael
M
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Garay
Julio
J
Chen
Di
D
Cui
Cindy
C
Turos
Edward
E
Dou
Q Ping
QP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D018922:HL-60 Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; D047090:beta-Lactams; D011065:Poly(ADP-ribose) Polymerases