title: Evaluation of the molecular mechanisms of a palladium(II) saccharinate complex with terpyridine as an anticancer agent.
abstract: Metal-based compounds represent promising anticancer therapeutic agents. In this study, the mechanism of action of a novel metal-based drug, a palladium(II) (Pd) complex ([PdCl(terpy)](sac)·2H2O, terpy=2,2':6',2''-terpyridine and sac=saccharinate), was elucidated. The tested compound induced cytotoxicity in nine different human cancer cell lines that originated from various organs, suggesting a broad spectrum of activity. The IC50 values were significantly higher for noncancerous cells when compared with cancer cells. We found that cells treated with the Pd(II) complex exhibited increased caspase 3/7 activities and condensed/fragmented nuclei, as demonstrated by nuclear staining and DNA laddering. Morphological features, such as cellular shrinkage and blebbing, were also observed, indicating that apoptosis was the primary mechanism of cell death. Pd(II) treatment induced DNA double-stranded breaks both in vitro and in vivo, potentially accounting for the source of stress in these cells. Although caspase 3/7 activities were elevated after Pd(II) treatment, silencing or using inhibitors of caspase 3 did not block apoptosis. Other molecules that could potentially play a role in Pd(II)-induced apoptosis, such as p53 and Bax, were also tested using silencing technology. However, none of these proteins were essential for cell death, indicating either that these molecules do not participate in Pd(II)-induced apoptosis or that other pathways were activated in their absence. Hence, this new molecule might represent a promising anticancer agent that exhibits cytotoxicity in p53-mutant, Bax-mutant, and/or caspase 3-mutant cancer cells.
authors.affiliation: aTUBITAK, Marmara Research Center, Genetic Engineering and Biotechnology Institute, Kocaeli Departments of bChemistry cBiology, Faculty of Arts and Sciences dDepartment of Medical Biochemistry, Medical School, Uludag University, Bursa eDepartment of Molecular Biology and Genetics, Faculty of Arts and Sciences, Istanbul University, Istanbul, Turkey.
authors.forename: Omer
authors.initials: O
authors.lastname: Kacar
authors.forename: Zelal
authors.initials: Z
authors.lastname: Adiguzel
authors.forename: Veysel T
authors.initials: VT
authors.lastname: Yilmaz
authors.forename: Yuksel
authors.initials: Y
authors.lastname: Cetin
authors.forename: Buse
authors.initials: B
authors.lastname: Cevatemre
authors.forename: Nazli
authors.initials: N
authors.lastname: Arda
authors.forename: Ahmet T
authors.initials: AT
authors.lastname: Baykal
authors.forename: Engin
authors.initials: E
authors.lastname: Ulukaya
authors.forename: Ceyda
authors.initials: C
authors.lastname: Acilan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D010165:Palladium / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010165:Palladium