ABSTRACT
A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.
Subject(s)
Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , G1 Phase/drug effects , Platinum/pharmacology , Triazines/chemical synthesis , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cattle , Cell Line, Tumor , Computer Simulation , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Drug Screening Assays, Antitumor , Female , Humans , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Platinum/therapeutic use , Protein Binding , Structure-Activity Relationship , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , Triazines/pharmacology , Tumor Suppressor Protein p53/metabolismABSTRACT
Epidermal growth factor (EGF) caused an increase in phosphoinositide (PI) turnover in MDA 468 cells. This EGF-stimulated effect was inhibited by the protein tyrosine kinase inhibitor lavendustin A (LA). MDA 468 cells generated an atypical PI turnover profile. Examination and quantitation of the PI metabolite profile showed that even control cells produced a metabolite which was acid-labile and which formed about 60% of the total PI metabolites. By using the technique of electrospray ionization tandem mass spectrometry, we were able to confirm the identity of this acid-labile metabolite through the specific fragmentation as compared with the standard. The precursor molecule fragmented into two distinct productions with molar masses identical to that of the standard myo-inositol 1,2-cyclic monophosphate (cInsP). Changes in the PI turnover profile could be accounted for by the alterations in myo-inositol 1,2-cyclic monophosphate generated in these cells. We thus conclude that, by some as-yet-unidentified mechanism, cyclic inositol monophosphate forms a major constituent of EGF-stimulated PI turnover in MDA 468 cells.
