A new platinum complex of triazine demonstrates G1 arrest with novel biological profile in human breast cancer cell line, MDA-MB-468.
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.
Mandal
Soma
S
Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
Bérubé
Gervais
G
Asselin
Eric
E
Richardson
Vernon J
VJ
Church
Jon G
JG
Bridson
John
J
Pham
Tram N Q
TN
Pramanik
Saroj K
SK
Mandal
Sanat K
SK
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002417:Cattle; D045744:Cell Line, Tumor; D003198:Computer Simulation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D010984:Platinum / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009942:Organometallic Compounds; C000606290:SOD1 protein, human; D014227:Triazines; D016159:Tumor Suppressor Protein p53; D010984:Platinum; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1