title: Anticancer activity and mode of action of titanocene C.
abstract: Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC₅₀ value of 48.3 ± 32.5 µM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for titanocene C and absent for titanocene Y in variant HL-60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIα, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to titanocene C. Approximately 50% of those genes downregulated by titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of titanocene C and metallothioneins as putative main effectors of drug resistance.
authors.affiliation: Ludwig Boltzmann Cluster of Translational Oncology, c/o Balderichgasse 26/13, A-1170, Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Olszewski
authors.forename: James
authors.initials: J
authors.lastname: Claffey
authors.forename: Megan
authors.initials: M
authors.lastname: Hogan
authors.forename: Matthias
authors.initials: M
authors.lastname: Tacke
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hamilton
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology*; D010984:Platinum / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C551172:bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV); D010984:Platinum