title: Comparative analyses of cytotoxicity and molecular mechanisms between platinum metallointercalators and cisplatin.
abstract: Platinum(II) metallointercalators of the type [Pt(I(L))(A(L))](2+), such as [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)](2+) (56MESS), are structurally different from cisplatin. This study, using a comparative transcriptomics approach, uncovered genomic expression patterns and molecular pathways that distinctively differentiated 56MESS and cisplatin in the eukaryote model organism Saccharomyces cerevisiae (yeast). Down-regulation of sulfur assimilation, cellular respiration, and energy metabolism were characteristics of 56MESS while up-regulation of these pathways and genes in cell cycle was the action of cisplatin. Furthermore, de novo purine biosynthesis and glycine metabolism were induced by 56MESS but suppressed by cisplatin. Different effects on intracellular concentrations of iron and copper were evident, with 56MESS more profoundly inducing genes controlling uptake of these ions than cisplatin. Finally, apart from 56MESS, additional metallointercalators including 56MEEN, 5MERR and 5MESS were subsequently identified to be more active in a cisplatin-resistant mouse leukaemia L1210cisR cell line than cisplatin, which provides multiple lead compounds for future drug development.
authors: School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith South DC, NSW, 2751, Australia.
authors: Shaoyu
authors: S
authors: Wang
authors: Ming J
authors: MJ
authors: Wu
authors: Vincent J
authors: VJ
authors: Higgins
authors: Janice R
authors: JR
authors: Aldrich-Wright
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013054:Spectrophotometry, Atomic; D015854:Up-Regulation / Q000235:genetics
chemical_list: C539772:(1,2-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)platinum(II); D007364:Intercalating Agents; D009944:Organoplatinum Compounds; D010984:Platinum; D002945:Cisplatin