TY - JOUR
T1 - Comparative analyses of cytotoxicity and molecular mechanisms between platinum metallointercalators and cisplatin
AU - Wang, Shaoyu
AU - Wu, Ming J.
AU - Higgins, Vincent J.
AU - Aldrich-Wright, Janice R.
PY - 2012
Y1 - 2012
N2 - Platinum(ii) metallointercalators of the type [Pt(IL)(AL)]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.
AB - Platinum(ii) metallointercalators of the type [Pt(IL)(AL)]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.
KW - cisplatin
KW - platinum compounds
KW - yeast
UR - http://handle.uws.edu.au:8081/1959.7/517699
U2 - 10.1039/c2mt20102j
DO - 10.1039/c2mt20102j
M3 - Article
SN - 1756-5901
VL - 4
SP - 950
EP - 959
JO - Metallomics
JF - Metallomics
IS - 9
ER -