Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride

M Guo, Hongyue Sun, Harry J McArdle, Lorraine Gambling, P J Sadler

Research output: Contribution to journalArticle

206 Citations (Scopus)

Abstract

The organometallic anticancer agent titanocene dichloride, Cp(2)TiCl(2), is now in phase II clinical trials as an anticancer drug, but its mechanism of action is poorly understood. We show here that the interactions of Cp(2)TiCl(2) with human serum transferrin (hTF) and that of Ti(2)-hTF with adenosine triphosphate (ATP) have characteristics that could allow transferrin to act as a mediator for titanium delivery to tumor cells. Such reactions may therefore be important to the anticancer activity of this new class of drugs. Cp(2)TiCl(2) reacts rapidly with human apo-transferrin under physiological conditions (100 mM NaCl, 25 mM bicarbonate, and 4 mM phosphate, pH 7.4) with carbonate as a synergistic anion. The Cp ligands are released from the drug. Two-dimensional [(1)H, (13)C] NMR studies of epsilon-[(13)C]Met-hTF show that Ti(IV) loads the C-lobe first followed by the N-lobe and binds in the specific Fe(III) sites. The protein conformational changes induced by Ti(IV) appear to be similar to those induced by Fe(III). Carbonate can act as a synergistic anion in Ti(2)-hTF but does not appear to be essential. A specific Ti(IV)-hTF adduct is formed even in the absence of bicarbonate. When the pH of Ti(2)-hTF solutions is lowered, no Ti(IV) is released at the endosomal pH of ca. 5.0-5.5, but one Ti(IV) dissociates between pH 4.5-2.0. In contrast, in the presence of 1 mM ATP, all Ti(IV) is readily released from both lobes when the pH is lowered from 7.0 to 4.5. Moreover, Fe(III) displaces Ti(IV) rapidly from the C-lobe of Ti(2)-hTF (
Original languageEnglish
Pages (from-to)10023-33
Number of pages11
JournalBiochemistry
Volume39
Issue number33
Publication statusPublished - 22 Aug 2000

Fingerprint

Transferrin
Cells
Serum
Pharmaceutical Preparations
Neoplasms
Carbonates
Bicarbonates
Anions
Adenosine Triphosphate
titanocene dichloride
Phase II Clinical Trials
Organometallics
Titanium
Antineoplastic Agents
Tumors
Phosphates
Nuclear magnetic resonance
Ligands

Keywords

  • Adenosine Triphosphate
  • Antineoplastic Agents
  • Endosomes
  • Female
  • Ferric Compounds
  • Glycosylation
  • Humans
  • Hydrogen-Ion Concentration
  • Iron
  • Neoplasms
  • Nuclear Magnetic Resonance, Biomolecular
  • Organometallic Compounds
  • Placenta Diseases
  • Pregnancy
  • Protein Processing, Post-Translational
  • Spectrophotometry
  • Spectrophotometry, Atomic
  • Titanium
  • Transferrin

Cite this

Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride. / Guo, M; Sun, Hongyue; McArdle, Harry J; Gambling, Lorraine; Sadler, P J.

In: Biochemistry, Vol. 39, No. 33, 22.08.2000, p. 10023-33.

Research output: Contribution to journalArticle

@article{d96fb54e8d324b9e9ff2bab8ac5848a2,
title = "Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride",
abstract = "The organometallic anticancer agent titanocene dichloride, Cp(2)TiCl(2), is now in phase II clinical trials as an anticancer drug, but its mechanism of action is poorly understood. We show here that the interactions of Cp(2)TiCl(2) with human serum transferrin (hTF) and that of Ti(2)-hTF with adenosine triphosphate (ATP) have characteristics that could allow transferrin to act as a mediator for titanium delivery to tumor cells. Such reactions may therefore be important to the anticancer activity of this new class of drugs. Cp(2)TiCl(2) reacts rapidly with human apo-transferrin under physiological conditions (100 mM NaCl, 25 mM bicarbonate, and 4 mM phosphate, pH 7.4) with carbonate as a synergistic anion. The Cp ligands are released from the drug. Two-dimensional [(1)H, (13)C] NMR studies of epsilon-[(13)C]Met-hTF show that Ti(IV) loads the C-lobe first followed by the N-lobe and binds in the specific Fe(III) sites. The protein conformational changes induced by Ti(IV) appear to be similar to those induced by Fe(III). Carbonate can act as a synergistic anion in Ti(2)-hTF but does not appear to be essential. A specific Ti(IV)-hTF adduct is formed even in the absence of bicarbonate. When the pH of Ti(2)-hTF solutions is lowered, no Ti(IV) is released at the endosomal pH of ca. 5.0-5.5, but one Ti(IV) dissociates between pH 4.5-2.0. In contrast, in the presence of 1 mM ATP, all Ti(IV) is readily released from both lobes when the pH is lowered from 7.0 to 4.5. Moreover, Fe(III) displaces Ti(IV) rapidly from the C-lobe of Ti(2)-hTF (",
keywords = "Adenosine Triphosphate, Antineoplastic Agents, Endosomes, Female, Ferric Compounds, Glycosylation, Humans, Hydrogen-Ion Concentration, Iron, Neoplasms, Nuclear Magnetic Resonance, Biomolecular, Organometallic Compounds, Placenta Diseases, Pregnancy, Protein Processing, Post-Translational, Spectrophotometry, Spectrophotometry, Atomic, Titanium, Transferrin",
author = "M Guo and Hongyue Sun and McArdle, {Harry J} and Lorraine Gambling and Sadler, {P J}",
year = "2000",
month = "8",
day = "22",
language = "English",
volume = "39",
pages = "10023--33",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "33",

}

TY - JOUR

T1 - Ti(IV) uptake and release by human serum transferrin and recognition of Ti(IV)-transferrin by cancer cells: understanding the mechanism of action of the anticancer drug titanocene dichloride

AU - Guo, M

AU - Sun, Hongyue

AU - McArdle, Harry J

AU - Gambling, Lorraine

AU - Sadler, P J

PY - 2000/8/22

Y1 - 2000/8/22

N2 - The organometallic anticancer agent titanocene dichloride, Cp(2)TiCl(2), is now in phase II clinical trials as an anticancer drug, but its mechanism of action is poorly understood. We show here that the interactions of Cp(2)TiCl(2) with human serum transferrin (hTF) and that of Ti(2)-hTF with adenosine triphosphate (ATP) have characteristics that could allow transferrin to act as a mediator for titanium delivery to tumor cells. Such reactions may therefore be important to the anticancer activity of this new class of drugs. Cp(2)TiCl(2) reacts rapidly with human apo-transferrin under physiological conditions (100 mM NaCl, 25 mM bicarbonate, and 4 mM phosphate, pH 7.4) with carbonate as a synergistic anion. The Cp ligands are released from the drug. Two-dimensional [(1)H, (13)C] NMR studies of epsilon-[(13)C]Met-hTF show that Ti(IV) loads the C-lobe first followed by the N-lobe and binds in the specific Fe(III) sites. The protein conformational changes induced by Ti(IV) appear to be similar to those induced by Fe(III). Carbonate can act as a synergistic anion in Ti(2)-hTF but does not appear to be essential. A specific Ti(IV)-hTF adduct is formed even in the absence of bicarbonate. When the pH of Ti(2)-hTF solutions is lowered, no Ti(IV) is released at the endosomal pH of ca. 5.0-5.5, but one Ti(IV) dissociates between pH 4.5-2.0. In contrast, in the presence of 1 mM ATP, all Ti(IV) is readily released from both lobes when the pH is lowered from 7.0 to 4.5. Moreover, Fe(III) displaces Ti(IV) rapidly from the C-lobe of Ti(2)-hTF (

AB - The organometallic anticancer agent titanocene dichloride, Cp(2)TiCl(2), is now in phase II clinical trials as an anticancer drug, but its mechanism of action is poorly understood. We show here that the interactions of Cp(2)TiCl(2) with human serum transferrin (hTF) and that of Ti(2)-hTF with adenosine triphosphate (ATP) have characteristics that could allow transferrin to act as a mediator for titanium delivery to tumor cells. Such reactions may therefore be important to the anticancer activity of this new class of drugs. Cp(2)TiCl(2) reacts rapidly with human apo-transferrin under physiological conditions (100 mM NaCl, 25 mM bicarbonate, and 4 mM phosphate, pH 7.4) with carbonate as a synergistic anion. The Cp ligands are released from the drug. Two-dimensional [(1)H, (13)C] NMR studies of epsilon-[(13)C]Met-hTF show that Ti(IV) loads the C-lobe first followed by the N-lobe and binds in the specific Fe(III) sites. The protein conformational changes induced by Ti(IV) appear to be similar to those induced by Fe(III). Carbonate can act as a synergistic anion in Ti(2)-hTF but does not appear to be essential. A specific Ti(IV)-hTF adduct is formed even in the absence of bicarbonate. When the pH of Ti(2)-hTF solutions is lowered, no Ti(IV) is released at the endosomal pH of ca. 5.0-5.5, but one Ti(IV) dissociates between pH 4.5-2.0. In contrast, in the presence of 1 mM ATP, all Ti(IV) is readily released from both lobes when the pH is lowered from 7.0 to 4.5. Moreover, Fe(III) displaces Ti(IV) rapidly from the C-lobe of Ti(2)-hTF (

KW - Adenosine Triphosphate

KW - Antineoplastic Agents

KW - Endosomes

KW - Female

KW - Ferric Compounds

KW - Glycosylation

KW - Humans

KW - Hydrogen-Ion Concentration

KW - Iron

KW - Neoplasms

KW - Nuclear Magnetic Resonance, Biomolecular

KW - Organometallic Compounds

KW - Placenta Diseases

KW - Pregnancy

KW - Protein Processing, Post-Translational

KW - Spectrophotometry

KW - Spectrophotometry, Atomic

KW - Titanium

KW - Transferrin

M3 - Article

VL - 39

SP - 10023

EP - 10033

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 33

ER -