[RuII5-C5H5 (bipy)(PPh3)]+, a promising large spectrum antitumor agent

Cytotoxic activity and interaction with human serum albumin

Ana Isabel Tomaz, T. Jakusch, Tânia S. Morais, Fernanda Marques, Rodrigo F M De Almeida, Filipa Mendes, E. Enyedy, Isabel Santos, João Costa Pessoa, T. Kiss, M. Helena Garcia

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy. We present results on the in vitro antitumor activity of an organometallic 'RuIICp' complex, [RuIICp(bipy)(PPh 3)][CF3SO3], designated as TM34 (PPh 3 = triphenylphosphine; bipy = 2,2′-bipyridine), against a panel of human tumor cell lines with different responses to cisplatin treatment, namely ovarian (A2780/A2780cisR, cisplatin sensitive and resistant, respectively), breast (MCF7) and prostate (PC3) adenocarcinomas. TM34 is very active against all tumorigenic cell lines, its efficacy largely surpassing that of cisplatin (CisPt). The high activity of TM34 towards CisPt resistant cell lines possibly suggests a mechanism of action distinct from that of CisPt. The effect of TM34 on the activity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) involved in DNA repair mechanisms and apoptotic pathways was also evaluated, and it was found to be a strong PARP-1 ruthenium inhibitor in the low micromolar range (IC50 = 1.0 ± 0.3 μM). TM34 quickly binds to human serum albumin forming a 1:1 complex with a conditional stability constant (log K' ∼ 4.0), comparable to that of the RuIII complex in clinical trial KP1019. This indicates that TM34 can be efficiently transported by this protein, possibly being involved in its distribution and delivery if the complex is introduced in the blood stream. Albumin binding does not affect TM34 activity, yielding an adduct that maintains cytotoxic properties (against A2780 and A2780cisR cells). Altogether, the properties herein evaluated suggest that TM34 could be an anticancer agent of highly relevant therapeutic value.

Original languageEnglish
Pages (from-to)261-269
Number of pages9
JournalJournal of Inorganic Biochemistry
Volume117
DOIs
Publication statusPublished - Dec 2012

Fingerprint

Serum Albumin
Antineoplastic Agents
Cisplatin
Ruthenium
Poly(ADP-ribose) Polymerases
Cells
Cell Line
Chemotherapy
Organometallics
Tumor Cell Line
DNA Repair
Inhibitory Concentration 50
Tumors
Prostate
Albumins
Adenocarcinoma
Breast
Repair
Blood
Clinical Trials

Keywords

  • Anti-tumor activity
  • Cyclopentadienyl
  • Cytotoxicity
  • Human serum albumin-binding
  • PARP-1 inhibitor
  • Ruthenium(II)

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

[RuII5-C5H5 (bipy)(PPh3)]+, a promising large spectrum antitumor agent : Cytotoxic activity and interaction with human serum albumin. / Tomaz, Ana Isabel; Jakusch, T.; Morais, Tânia S.; Marques, Fernanda; De Almeida, Rodrigo F M; Mendes, Filipa; Enyedy, E.; Santos, Isabel; Pessoa, João Costa; Kiss, T.; Garcia, M. Helena.

In: Journal of Inorganic Biochemistry, Vol. 117, 12.2012, p. 261-269.

Research output: Contribution to journalArticle

Tomaz, Ana Isabel ; Jakusch, T. ; Morais, Tânia S. ; Marques, Fernanda ; De Almeida, Rodrigo F M ; Mendes, Filipa ; Enyedy, E. ; Santos, Isabel ; Pessoa, João Costa ; Kiss, T. ; Garcia, M. Helena. / [RuII5-C5H5 (bipy)(PPh3)]+, a promising large spectrum antitumor agent : Cytotoxic activity and interaction with human serum albumin. In: Journal of Inorganic Biochemistry. 2012 ; Vol. 117. pp. 261-269.
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abstract = "Ruthenium complexes hold great potential as alternatives to cisplatin in cancer chemotherapy. We present results on the in vitro antitumor activity of an organometallic 'RuIICp' complex, [RuIICp(bipy)(PPh 3)][CF3SO3], designated as TM34 (PPh 3 = triphenylphosphine; bipy = 2,2′-bipyridine), against a panel of human tumor cell lines with different responses to cisplatin treatment, namely ovarian (A2780/A2780cisR, cisplatin sensitive and resistant, respectively), breast (MCF7) and prostate (PC3) adenocarcinomas. TM34 is very active against all tumorigenic cell lines, its efficacy largely surpassing that of cisplatin (CisPt). The high activity of TM34 towards CisPt resistant cell lines possibly suggests a mechanism of action distinct from that of CisPt. The effect of TM34 on the activity of the enzyme poly(ADP-ribose) polymerase 1 (PARP-1) involved in DNA repair mechanisms and apoptotic pathways was also evaluated, and it was found to be a strong PARP-1 ruthenium inhibitor in the low micromolar range (IC50 = 1.0 ± 0.3 μM). TM34 quickly binds to human serum albumin forming a 1:1 complex with a conditional stability constant (log K' ∼ 4.0), comparable to that of the RuIII complex in clinical trial KP1019. This indicates that TM34 can be efficiently transported by this protein, possibly being involved in its distribution and delivery if the complex is introduced in the blood stream. Albumin binding does not affect TM34 activity, yielding an adduct that maintains cytotoxic properties (against A2780 and A2780cisR cells). Altogether, the properties herein evaluated suggest that TM34 could be an anticancer agent of highly relevant therapeutic value.",
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AU - Morais, Tânia S.

AU - Marques, Fernanda

AU - De Almeida, Rodrigo F M

AU - Mendes, Filipa

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