Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies

DV Luis, J Silva, AI Tomaz, RFM de Almeida, M Larguinho, Pedro V. Baptista, LMDRS Martins, TFS Silva, PM Borralho, CMP Rodrigues, A.S. Rodrigues, AJL Pombeiro, Alexandra R. Fernandes

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The very high antiproliferative activity of {[}Co(Cl)(H2O)(phendione)(2)]{[}BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that {[}Co(Cl)(phendione)(2)(H2O)]{[}BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 \% at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.}}}}
Original languageUnknown
Pages (from-to)787-803
JournalJournal Of Biological Inorganic Chemistry
Volume19
Issue number6
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Cobalt
  • 1,10-Phenanthroline-5,6-dione
  • Apoptosis
  • DNA cleavage
  • Human serum albumin

Cite this

Luis, DV ; Silva, J ; Tomaz, AI ; de Almeida, RFM ; Larguinho, M ; Baptista, Pedro V. ; Martins, LMDRS ; Silva, TFS ; Borralho, PM ; Rodrigues, CMP ; Rodrigues, A.S. ; Pombeiro, AJL ; Fernandes, Alexandra R. / Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies. In: Journal Of Biological Inorganic Chemistry. 2014 ; Vol. 19, No. 6. pp. 787-803.
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abstract = "The very high antiproliferative activity of {[}Co(Cl)(H2O)(phendione)(2)]{[}BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that {[}Co(Cl)(phendione)(2)(H2O)]{[}BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 \{\%} at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.}}}}",
keywords = "ANTITUMOR-ACTIVITY, CANCER-CELLS, Apoptosis, Human serum albumin, CLEAVAGE ACTIVITY, Cobalt, 1,10-Phenanthroline-5,6-dione, HETEROCYCLIC BASES, URSODEOXYCHOLIC ACID, HUMAN-SERUM-ALBUMIN, DNA cleavage, METAL-COMPLEXES, RUTHENIUM COMPLEXES, COPPER(II) COMPLEXES, NUCLEASE ACTIVITY, Cobalt, 1,10-Phenanthroline-5,6-dione, Apoptosis, DNA cleavage, Human serum albumin",
author = "DV Luis and J Silva and AI Tomaz and {de Almeida}, RFM and M Larguinho and Baptista, {Pedro V.} and LMDRS Martins and TFS Silva and PM Borralho and CMP Rodrigues and A.S. Rodrigues and AJL Pombeiro and Fernandes, {Alexandra R.}",
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Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies. / Luis, DV; Silva, J; Tomaz, AI; de Almeida, RFM; Larguinho, M ; Baptista, Pedro V.; Martins, LMDRS; Silva, TFS; Borralho, PM ; Rodrigues, CMP ; Rodrigues, A.S.; Pombeiro, AJL; Fernandes, Alexandra R.

In: Journal Of Biological Inorganic Chemistry, Vol. 19, No. 6, 01.01.2014, p. 787-803.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies

AU - Luis, DV

AU - Silva, J

AU - Tomaz, AI

AU - de Almeida, RFM

AU - Larguinho, M

AU - Baptista, Pedro V.

AU - Martins, LMDRS

AU - Silva, TFS

AU - Borralho, PM

AU - Rodrigues, CMP

AU - Rodrigues, A.S.

AU - Pombeiro, AJL

AU - Fernandes, Alexandra R.

N1 - PMID:24481501 WOS:000339975100007

PY - 2014/1/1

Y1 - 2014/1/1

N2 - The very high antiproliferative activity of {[}Co(Cl)(H2O)(phendione)(2)]{[}BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that {[}Co(Cl)(phendione)(2)(H2O)]{[}BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 \% at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.}}}}

AB - The very high antiproliferative activity of {[}Co(Cl)(H2O)(phendione)(2)]{[}BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that {[}Co(Cl)(phendione)(2)(H2O)]{[}BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 \% at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.}}}}

KW - ANTITUMOR-ACTIVITY

KW - CANCER-CELLS

KW - Apoptosis

KW - Human serum albumin

KW - CLEAVAGE ACTIVITY

KW - Cobalt

KW - 1,10-Phenanthroline-5,6-dione

KW - HETEROCYCLIC BASES

KW - URSODEOXYCHOLIC ACID

KW - HUMAN-SERUM-ALBUMIN

KW - DNA cleavage

KW - METAL-COMPLEXES

KW - RUTHENIUM COMPLEXES

KW - COPPER(II) COMPLEXES

KW - NUCLEASE ACTIVITY

KW - Cobalt

KW - 1,10-Phenanthroline-5,6-dione

KW - Apoptosis

KW - DNA cleavage

KW - Human serum albumin

U2 - 10.1007/s00775-014-1110-0

DO - 10.1007/s00775-014-1110-0

M3 - Article

VL - 19

SP - 787

EP - 803

JO - Journal Of Biological Inorganic Chemistry

JF - Journal Of Biological Inorganic Chemistry

SN - 0949-8257

IS - 6

ER -