Cytotoxicity and DNA damage induced by a new platinum(II) complex with pyridine and dithiocarbamate.
A new platinum(II) complex containing a pyridine nucleus and a dithiocarbamate moiety as ligands ([Pt(ESDT)(Py)Cl]) was evaluated for in vitro cytotoxicity in the cisplatin-sensitive human ovarian 2008 and in the isogenic-resistant C13* cell lines. In both cell types, a tumor cell growth inhibition greater than cisplatin and a complete lack of cross-resistance in C13* cells were found. Despite its molecular size, [Pt(ESDT)(Py)Cl] accumulation was much higher than cisplatin both in parent and resistant cells. Studying the mechanism of action in cell-free media, we established that [Pt(ESDT)(Py)Cl] more efficiently interacts with DNA in vitro compared to cisplatin maintaining a binding preference for GG rich sequences of DNA. On the contrary, DNA platination in vivo by [Pt(ESDT)(Py)Cl] was found lower than cisplatin. An analysis of the type of DNA lesions induced by [Pt(ESDT)(Py)Cl] suggests that the cytotoxic efficacy and the ability to overcome cisplatin resistance seem to be related to a different mechanism of interaction with DNA and/or with other key cellular components.
Department of Pharmaceutical Chemistry, University of Padova, Centro di Studio sulla Chimica del Farmaco e dei Prodotti Biologicamente Attivi del C.N.R., Via Marzolo 5, Padova, Italy. cristina.marzano@unipd.it
Cristina
C
Marzano
Dolores
D
Fregona
Francarosa
F
Baccichetti
Andrea
A
Trevisan
Lorena
L
Giovagnini
Franco
F
Bordin
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002417:Cattle; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D011725:Pyridines; D013859:Thiocarbamates; D004247:DNA; D002945:Cisplatin