Synthesis, Anticancer Activity, and Genome Profiling of Thiazolo Arene Ruthenium Complexes.
Sixteen hydrazinyl-thiazolo arene ruthenium complexes of the general formula [(η(6)-p-cymene)Ru(N,N'-hydrazinyl-thiazolo)Cl]Cl were synthesized. All complexes were tested in vitro for their antiproliferative activity on three tumor cell lines (HeLa, A2780, and A2780cisR) and on a noncancerous cell line (HFL-1). A superior cytotoxic activity of the ruthenium complexes as compared to cisplatin and oxaliplatin, on both cisplatin-sensitive and cisplatin resistant ovarian cancer cells, was observed. In addition, the biological activity of two selected derivatives was evaluated using microarray gene expression assay and ingenuity pathway analysis. p53 signaling was identified as an important pathway modulated by both arene ruthenium compounds. New activated molecules such as FAS, ZMAT3, PRMT2, BBC3/PUMA, and PDCD4, whose overexpressions are correlated with overcoming resistance to cisplatin therapy, were also identified as potential targets. Moreover, the arene ruthenium complexes can be used in association with cisplatin to prevent cisplatin resistance development and synergistically to induce cell death in ovarian cancer cells.
Faculty of Pharmacy, "Iuliu Hatieganu" University of Medicine and Pharmacy , Victor Babes Str. 41, RO-400012 Cluj-Napoca, Romania.
Adriana
A
Grozav
Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuta" , 34-36 Republicii Str, RO-400015, Cluj-Napoca, Romania.
Ovidiu
O
Balacescu
Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuta" , 34-36 Republicii Str, RO-400015, Cluj-Napoca, Romania.
Loredana
L
Balacescu
Institut de Chimie, Université de Neuchâtel , 51 Avenue de Bellevaux, CH-2000 Neuchâtel, Switzerland.
Thomas
T
Cheminel
Department of Functional Genomics, Proteomics and Experimental Pathology, The Oncology Institute "Prof Dr. Ion Chiricuta" , 34-36 Republicii Str, RO-400015, Cluj-Napoca, Romania.|Research Center of Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hatieganu″ University of Medicine and Pharmacy , 23 Marinescu Str, RO-400337 Cluj-Napoca, Romania.
Ioana
I
Berindan-Neagoe
Institut de Chimie, Université de Neuchâtel , 51 Avenue de Bellevaux, CH-2000 Neuchâtel, Switzerland.
Bruno
B
Therrien
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D000081007:Cymenes; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D039821:Monoterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059467:Transcriptome
D000970:Antineoplastic Agents; D000081007:Cymenes; D039821:Monoterpenes; D013844:Thiazoles; C007210:4-cymene; D012428:Ruthenium; D002945:Cisplatin