Combination of Genistein and Cisplatin with Two Designed Monofunctional Platinum Agents in Human Ovarian Tumour Models.
A great amount of research effort has been directed at platinum compounds that bind with DNA differently from cisplatin with the idea that the difference may translate into an altered spectrum of activity. Recently research has also been directed at applying combinations of platinum agents with tumour-active phytochemicals with the aim of providing a means of overcoming platinum resistance in ovarian cancer. Herein we report the synthesis of monofunctional platinum tris(3-hydroxypyridine)chloroplatinum(II) chloride (coded as LH1) and tris(imidazole)chloroplatinum(II) chloride (coded as LH2), and their activity alone and in combination with genistein and cisplatin against human ovarian A2780, cisplatin-resistant A2780(cisR) and picoplatin-resistant A2780(ZD0473R) cancer cell lines. Although both LH1 and LH2 were found to be less active than cisplatin against the tumour models, they produced synergistic outcomes in combination with genistein. Both the level of cellular accumulation of Pt and of Pt-DNA binding resulting from the combination were greater in the A2780(cisR) cell line than in the parental A2780 cell line, irrespective of the sequence of administration. Absence of association between activity of LH1 and LH2 and the level of Pt-DNA binding indicates that the cell death induced by LH1 and LH2 may not be limited to the effect of their binding with DNA.
Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia.
Laila
L
Arzuman
Sydney Cancer Centre, Concord Repatriation Hospital, Concord, NSW, Australia.
Philip
P
Beale
School of Chemistry, The University of Sydney, Sydney, NSW, Australia.
Nick
N
Proschogo
Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia.
Jun Q
JQ
Yu
Discipline of Biomedical Science, Sydney Medical School, The University of Sydney, Cumberland Campus, Lidcombe, NSW, Australia Fazlul.Huq@sydney.edu.au.
Fazlul
F
Huq
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D019833:Genistein / Q000008:administration & dosage; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C000604912:tris(3-hydroxypyridine)chloroplatinum(II); C000604913:tris(imidazole)chloroplatinum(II); D019833:Genistein; D002945:Cisplatin
3-hydroxypyridine; DNA fragmentation; Ovarian cancer; drug combination; drug resistance; imidazole