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Anticancer activity and mode of action of titanocene C

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Summary

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.

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Acknowledgment

This work was supported in part by a grant of the Austrian National Bank (# 13345).

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Authors and Affiliations

  1. Ludwig Boltzmann Cluster of Translational Oncology, c/o Balderichgasse 26/13, A-1170, Vienna, Austria

    Ulrike Olszewski, Robert Zeillinger & Gerhard Hamilton

  2. UCD School of Chemistry and Chemical Biology, University College Dublin, Dublin, Ireland

    James Claffey, Megan Hogan & Matthias Tacke

  3. Institute of Pharmacy, University of Greifswald, Greifswald, Germany

    Patrick J. Bednarski

Authors
  1. Ulrike Olszewski
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  2. James Claffey
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  3. Megan Hogan
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  4. Matthias Tacke
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  5. Robert Zeillinger
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  6. Patrick J. Bednarski
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  7. Gerhard Hamilton
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Correspondence to Gerhard Hamilton.

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Olszewski, U., Claffey, J., Hogan, M. et al. Anticancer activity and mode of action of titanocene C. Invest New Drugs 29, 607–614 (2011). https://doi.org/10.1007/s10637-010-9395-5

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  • DOI: https://doi.org/10.1007/s10637-010-9395-5

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