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Article: TiIV uptake and release by human serum transferrin and recognition of TiIV-transferrin by cancer cells: Understanding the mechanism of action of the anticancer drug titanocene dichloride

TitleTiIV uptake and release by human serum transferrin and recognition of TiIV-transferrin by cancer cells: Understanding the mechanism of action of the anticancer drug titanocene dichloride
Authors
Issue Date2000
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2000, v. 39 n. 33, p. 10023-10033 How to Cite?
AbstractThe organometallic anticancer agent titanocene dichloride, Cp 2TiCl 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 2TiCl 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 2TiCl 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 [ 1H, 13C] NMR studies of ε-[ 13C]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 (<5 min) but only slowly (days) from the N-lobe. Thus, the species Fe(C)Ti(N)-hTF might also provide a route for Ti(IV) entry into tumor cells via the transferrin receptor. Ti 2-hTF effectively blocked cell uptake of radiolabeled 59Fe-hTF into BeWo cells, a human placental choriocarcinoma cell line in culture. These results imply that titanium transferrin might be recognized by the transferrin receptor and be taken up into cancer cells.
Persistent Identifierhttp://hdl.handle.net/10722/167666
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGuo, Men_US
dc.contributor.authorSun, Hen_US
dc.contributor.authorMcardle, HJen_US
dc.contributor.authorGambling, Len_US
dc.contributor.authorSadler, PJen_US
dc.date.accessioned2012-10-08T03:09:38Z-
dc.date.available2012-10-08T03:09:38Z-
dc.date.issued2000en_US
dc.identifier.citationBiochemistry, 2000, v. 39 n. 33, p. 10023-10033en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/167666-
dc.description.abstractThe organometallic anticancer agent titanocene dichloride, Cp 2TiCl 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 2TiCl 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 2TiCl 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 [ 1H, 13C] NMR studies of ε-[ 13C]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 (<5 min) but only slowly (days) from the N-lobe. Thus, the species Fe(C)Ti(N)-hTF might also provide a route for Ti(IV) entry into tumor cells via the transferrin receptor. Ti 2-hTF effectively blocked cell uptake of radiolabeled 59Fe-hTF into BeWo cells, a human placental choriocarcinoma cell line in culture. These results imply that titanium transferrin might be recognized by the transferrin receptor and be taken up into cancer cells.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAdenosine Triphosphate - Metabolismen_US
dc.subject.meshAntineoplastic Agents - Metabolismen_US
dc.subject.meshEndosomes - Metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshFerric Compounds - Metabolismen_US
dc.subject.meshGlycosylationen_US
dc.subject.meshHumansen_US
dc.subject.meshHydrogen-Ion Concentrationen_US
dc.subject.meshIron - Metabolismen_US
dc.subject.meshNeoplasms - Metabolismen_US
dc.subject.meshNuclear Magnetic Resonance, Biomolecularen_US
dc.subject.meshOrganometallic Compounds - Metabolismen_US
dc.subject.meshPlacenta Diseases - Metabolismen_US
dc.subject.meshPregnancyen_US
dc.subject.meshProtein Processing, Post-Translationalen_US
dc.subject.meshSpectrophotometryen_US
dc.subject.meshSpectrophotometry, Atomicen_US
dc.subject.meshTitanium - Metabolismen_US
dc.subject.meshTransferrin - Metabolismen_US
dc.titleTiIV uptake and release by human serum transferrin and recognition of TiIV-transferrin by cancer cells: Understanding the mechanism of action of the anticancer drug titanocene dichlorideen_US
dc.typeArticleen_US
dc.identifier.emailSun, H:hsun@hkucc.hku.hken_US
dc.identifier.authoritySun, H=rp00777en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/bi000798zen_US
dc.identifier.pmid10955990-
dc.identifier.scopuseid_2-s2.0-0034702778en_US
dc.identifier.hkuros64438-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0034702778&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume39en_US
dc.identifier.issue33en_US
dc.identifier.spage10023en_US
dc.identifier.epage10033en_US
dc.identifier.isiWOS:000088945800002-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGuo, M=7201564747en_US
dc.identifier.scopusauthoridSun, H=7404827446en_US
dc.identifier.scopusauthoridMcArdle, HJ=7006225614en_US
dc.identifier.scopusauthoridGambling, L=6602825365en_US
dc.identifier.scopusauthoridSadler, PJ=7103024488en_US

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