Non-DNA-binding platinum anticancer agents: Cytotoxic activities of platinum-phosphato complexes towards human ovarian cancer cells.
DNA is believed to be the molecular target for the cytotoxic activities of platinum (Pt) anticancer drugs. We report here a class of platinum(II)- and platinum(IV)-pyrophosphato complexes that exhibit cytotoxicity comparable with and, in some cases, better than cisplatin in ovarian cell lines (A2780, A2780/C30, and CHO), yet they do not show any evidence of covalent binding to DNA. Moreover, some of these compounds are quite effective in cisplatin- and carboplatin-resistant cell line A2780/C30. The lack of DNA binding was demonstrated by the absence of a detectable Pt signal by atomic absorption spectroscopy using isolated DNA from human ovarian cells treated with a platinum(II)-pyrophosphato complex, (trans-1,2-cyclohexanediamine)(dihydrogen pyrophosphato) platinum(II), (pyrodach-2) and from NMR experiments using a variety of nucleotides including single- and double-stranded DNA. Furthermore, pyrodach-2 exhibited reduced cellular accumulations compared with cisplatin in cisplatin- and carboplatin-resistant human ovarian cells, yet the IC(50) value for the pyrophosphato complex was much less than that of cisplatin. Moreover, unlike cisplatin, pyrodach-2 treated cells overexpressed fas and fas-related transcription factors and some proapoptotic genes such as Bak and Bax. Data presented in this report collectively indicate that pyrodach-2 follows different cytotoxic mechanisms than does cisplatin. Unlike cisplatin, pyrodach-2 does not undergo aquation during 1 week and is quite soluble and stable in aqueous solutions. Results presented in this article represent a clear paradigm shift not only in expanding the molecular targets for Pt anticancer drugs but also in strategic development for more effective anticancer drugs.
Bose
Rathindra N
RN
Department of Biomedical Sciences, Ohio University, Athens, OH 45701, USA. bose@ohio.edu
Maurmann
Leila
L
Mishur
Robert J
RJ
Yasui
Linda
L
Gupta
Shefalika
S
Grayburn
W Scott
WS
Hofstetter
Heike
H
Salley
Tara
T
Milton
Tara
T
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010710:Phosphates / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013054:Spectrophotometry, Atomic
D000970:Antineoplastic Agents; D017931:DNA Primers; D009943:Organophosphorus Compounds; D010710:Phosphates; D004247:DNA