Cytotoxic Salan-Titanium(IV) Complexes: High Activity Toward a Range of Sensitive and Drug-Resistant Cell Lines, and Mechanistic Insights

Cesar M. Manna, Ori Braitbard, Esther Weiss, Jacob Hochman*, Edit Y. Tshuva

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

The cytotoxicities of highly efficient salan-Ti IV complexes toward a range of cell lines, including drug-resistant cells, are reported along with preliminary mechanistic insights. Five salan-Ti IV complexes were investigated toward eight different human and murine cancer-derived cell lines, including colon, ovarian, lung, cervical, pancreatic, leukemic, skin, and breast. The salan complexes are more active toward the cells analyzed than cisplatin and the known titanium compound (bzac) 2Ti(OiPr) 2, and no cell line resistant to the salan complexes was identified. Moreover, the salan-Ti IV complexes are highly active toward both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780CisR) human ovarian cancer cell lines. Similarly, the salan complexes are cytotoxic toward multi-drug-resistant (ABCB1-expressing) mouse lymphoma cell lines HU-1 and HU-2. Importantly, minimal or no activity was observed toward primary murine cells (bone marrow, heart, liver, kidney, spleen, and lung), supporting selectivity for cancer cells. Additionally, the salan complexes maintain high cytotoxicity for up to 24h following exposure to cell culture medium, whereas reference complexes (bzac) 2Ti(OiPr) 2 and Cp 2TiCl 2 rapidly lose much of their activity upon exposure to medium, within ~1h. The upregulation of p53 followed by cell-cycle arrest in G 1 phase is likely one mechanism of action of the salan complexes. Taken together, the results indicate that these compounds are selectively toxic to cancer cells and are able to circumvent two independent mechanisms of drug resistance, thus expanding the scope of their potential medicinal utility.

Original languageAmerican English
Pages (from-to)703-708
Number of pages6
JournalChemMedChem
Volume7
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • Antitumor agents
  • Apoptosis
  • Cisplatin
  • Cytotoxicity
  • Titanium(IV)

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