Gold(III) Compounds as a New Family of Antitumor Compounds

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Gold(Ill)

Compounds

as

New

Family

of

Anticancer

Drugs

Luigi

Messori*,

Giordana

Marcon

and

Pierluigi

Orioli

Department

_of

Chemistry,

University

_of

Florence,

viadellaLastruccia3,

50019

Sesto

Fiorentino

(Florence),

Italy.

(Received

February

2 l,

2003; Accepted

March

14, 2003)

ABSTRACT

Gold(III) complexes are emerging as a new class of metal complexes with outstanding cytotoxic

properties and arepresently beingevaluated aspotential antitumoragents. Thisrenewed interest is the result

of recent studies in which various gold(III) complexes have been shown to be stable under physiological

conditions andto manifest relevantantiproliferative properties against selected human tumor cell lines. The

pharmacological investigationof somerepresentative gold(III) complexes hasbeen extended to consider their

effects on the cell cycle and to reveal induction of apoptosis. Remarkably, preliminary studies suggest that

the interactions in vitro ofgold(Ill)complexes with calfthymus DNA are weakwhereas significant binding

to model proteins takes place. Our findings imply that the mechanism of action of cytotoxic gold(Ill)

complexesmight be substantiallydifferentfrom that of clinicallyestablishedplatinumcompounds.

GOLD(Ill) COMPLEXESASA POSSIBLEALTERNATIVETOPLATINUM COMPLEXES.

Following the discovery of the antiproliferative effects of cisplatin, attention was devoted to gold(III) complexes as apossible alternative to antitumor platinum drugs [1-3]. This interest mainly originated from

theobservation thatboth platinum(II)andgold(III)complexes possess thesame electronicconfiguration(d8)

and give rise preferentiallyto square planar complexes. Ligand exchangekinetics is relativelyslow in both

cases, although faster in gold(III) complexes. Thus, the strict relationship to platinum(If) compounds

renderedgold(III) complexes attractingcandidates fordevelopmentand testingaspotential anticancer drugs;

CorrespondingAuthor: Dr.LuigiMessori

Fax:+39 0554573385;Tel: +39 0554573284;

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Vol. l,No. 2, 2003

_Gold(Ill)

CompoundsasNewFamily

_of

Anticancer

Drugs

unfortunatelytheirrelativelypoor chemicalstabilityin solutionheavilyhinderedsuch studies for alongtime.

Thus, until the mid-90’s, only a few reportsexisted in the literature describingthe cytotoxic propertiesand

the in vivo antitumor effects ofgold(Ill) complexes

[4-6].

In some cases important systemic toxic effects,

produced bygold(Ill) complexes, had beenreported

[1]

and significant differences inthe spectrum of action

hadbeen noticed comparedtocisplatin.

STRUCTURAL FEATURESOFSOME GOLD(Ill) COMPLEXES.

Inrecentyears,owingto thecofitributionsofafewresearchgroups, newgold(Ill) compoundshave been

synthesized and characterized that show sufficient stability under physiologically relevant conditions. Such

stabilization is generally achieved through an appropriate choice ofthe ligands, in most cases bearing

nitrogenatomsasdonorgroups.Anumberofthesegold(llI)compoundsareshown inFigure 1.

Recently some organogold(III) compounds, bearing the bipyridyl moiety, have been developed by the group of Giovanni Minghettiin Sassari(Italy);.typicalcompounds of thisfamilyare shown in Figure 2(the

crystalstructures are availablefor mO;tof thesegold(Ill) complexes).

BEHAVIOUR INSOLUTION OF SELECTED GOLD(Ill) COMPLEXES.

Essential requirements for the pharmacological evaluation in vitro ofnewmetal complexes as cytotoxic

agentsare anappreciable solubilityin water and a sufficient chemical stability under

physiologically

relevant

conditions. Thus, prior to any biological testing, the chemical behaviour in solution of newly prepared

gold(III) complexes isanalysed in detail. The chemical characterization in solution is mainlyperformedwith

thehelpof variousspectroscopic techniques includingvisibleabsorption spectroscopy,

H

NMRand ESI-MS

[3]. Notably, most gold(Ill) complexes prepared in our laboratory exhibit characteristic and intense

transitions in the visible that have allowed us to test their time-dependent stability. Generally, the visible

spectra recordedafterdissolvingthe individual compoundsin the referencebuffer(phosphatebuffer,

pH

7.4,

NaCI 4raM or 100raM) do not showsignificantmodifications forseveral hours, implying that thegold(Ill)

chromophoredoesnotundergomajor transformations.Anexampleisshown inFigure3.

Subsequent application of ESI-MS and NMR techniques has allowed, in several cases, detailed

identification of thespecies that are dominant in solution [3]. Invariouscases,thestabilityofthesegold(Ill)

complexes has been firther assessed in RPMI, the culture medium used for the in vitro cytotoxicity experiments (unpublished results fromourlaboratory).

IN VITRO CYTOTOXICITY ASTHEMAIN SCREENING METHOD.

Screening of novel compounds for anticancer activity is a major issue for the discovery of new agents

with encouragingpharmacological properties. Presently,themethodadopted by NCI isbased oninvitrotests

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L. MessorietaL _{Bioinorganic Chemistry and Applications} Ci Ci

Au

N

c

At,(hpm) O O --’--NH2

FtN...ff’

GHAu H H

2CIO4"

CI"

Au(Cyclam) +

CH2CH3

H

c

C.--

N

_Au

o

/

c

Au(esal) CI 3+ H₂ H₂/

NAu

3cr" N

/

\N

H2

Au(en):

*-’+

Au

Cl" /

c

Au(phen) (CH3)2 u ----C Cl Au(drnamp) 2Cl" Au(dien)

---]2+

N u---- Cl 2C1" Au(terpy)

Fig. 1: Schematicdrawing ofsomegold(Ill)complexes.

[Au(bipy%H)(OH)](PF6)

PF6

_Au

HO

’/

OH

[Au(bipy)(OH)2](PF6)

PF6

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Vol. I, No.2, 2003

Gold(Ill)

CompoundsasNewFamily

of

Anticancer

Drugs

2.0 1.6 1.2 0.8 0.4

(I)

2,4 2,0 1,6 1.2 0.8 0,4 0,00 200,0

2zi0

(II)

280 320 360 400 440 480 500.0

L

(nm)

Electronicspectraof(I)Au(Cyclam)

lxl03M

atmixing(a)andafter72h(b); (II)Au(terpy)

1,2xl0M

atmixing(a)and after72h(b)in the reference buffer.

Thus,as afirststep for their pharmacological evaluation, the activity of some novelgold(Ill) complexes

developed in our laboratory was assayed against a small number of tumor cell lines. This restricted panel

comprised two ovarian carcinoma human cell lines, A2780 (both sensitive and resistant to cisplatin) and

SKOV3,the colon carcinorna HCT8 cell line and theT-lymphoblastoidleukemiaCCRF-CEM cell line(both

sensitive andresistant tocisplatin) [3]. Cell lines were maintained in RPMI 1640 medium supplementedwith

10% horse serum (CCRF-CEM/S, CCRF-CEM/R and HCT8) or fetal bovine serum _{(FBS) (SKOV3,}

A2780/S and _A2780/R) and antibiotics at 37C in a 5%

_CO2

atmosphere and subcultured twice weekly.

Experiments were conducted on exponentially growing cells. The Sulphorhodamine-B (SRB) assay was

performed in 96-well plates, using RPMI 1640 medium+ 5% FBS,according tothe protocol of Skehan [9].

The concentrationrange used for eachgold(lll) complexwasbetween 10"2

_.tM

and

_200.tM.

Notably,the

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L. Messorietal. Bioinorganic Chem.istry and Applications

Table1

EDso*

Values

(laM)

ofsomegold(III) compoundsinhumanovariancells A2780, bothsensitiveand

resistanttocisplatin, after 72 hoursofexposureto thedrugs.

EDso

(M)

Complex A2780/S exp.n. A2780/R exp.n.

Au(hpm) 10.1+1.0 3 21.0 2 Au(esal) 2.1+0.7 4 3.8+1.4 4 GHAu 5.2+1.6 3 8.5+2.3 3

Au(en)2

8.4+0.8 3 17.0+4.2 3 Au(dien) 8.2+_0.9 3 18.7+_2.2 3 Au(Cyclam) 99,0 2 > 120.0 3 Au(terpy ) 0.2 0.4+_0.03 3 Au(phen) 3.8+_1.1 5 3.5+_0.9 5 cisplatin 1.6+1.3 6 16.14-8.7 6 R/S 2.1 1.8 1.6 2.0 2.3 1.2 0.9 10.0

*Expressed

as mean+__SE_{of at}_{least three}_{determinations or mean}_of_{two determinations.}

aRatiobetween

_EDso

valuesonA2780/Rcells andon theparentalcellline.

It emerges that most gold(Ill) complexes are highly cytotoxic. Indeed, all investigated gold(Ill)

complexes -except Au(cyclam)- exhibited important cell killing properties toward the reference A2780/S

line, with

_EDs0

values falling in the micromolar range (from 0.3 to 10 gM). In some cases resistance to

cisplatinisclearlyovercome.

Table 2

EDo

(tuM)

values ofcisplatin,Au(phen)andAu(dien)in the human leukemic cellsCCRF-CEM,

sensitive or resistant tocisplatin. Datawerecollected72hrsafterremovingthedrugs.

ED.o

(tM)

Complex

Cisplatin Au(phen) Au(dien) lh 25.9+_4.2 169.2+7.1 >600 2hrs 9.1 128.7 500

CCRF-CEM

4hrs 5.3+1.2 98.6 259+-36.7 24hrs 0.9+-0.4 4.4 58.2

72hrs*

0.7+0.1 2.3 12.6

*Expressed

as mean + SE of at least three determinations or mean of two determinations. )" Ratiobetween

EDs0

values on CCRF-CEM/CDDP cells and on the parental cell line. * _Data _{were collected} _immediately

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Vol. 1, No. 2, 2003

Gold(Ill)

Compoundas_{New Famil),}

_of

Anticancer

Drugs

Table 3

EDs0

(gM)values ofcisplatin, Au(phen)andAu(dien)in the human leukemic cellsCCRF-CEM,

resistant tocisplatin. Datawerecollected 72 hrs afterremovingthedrugs.

EDso*

(tM) Complex Cisplatin Au(phen) Au(dien) lh >186 (>7) 214

(1.3)

>600 2hrs CCRF-CEM/R 4hrs 24hrs 29.4+1.1 (34) 111.9

(O.9)

59O

(1.2)

90

(0.9)

324 (1.3) 7.4 (1.7) 163.3+39 (.8)

72hrs*

6 (2.6) 32.7+6.6 (2.6)

*Expressed

as mean+ SEof atleast threedeterminations or meanoftwo determinations. ( ): Ratiobetween

EDs0

values on CCRF-CEM/CDDP cells and on the parental cell line. * _Data_were _{collected immediately}

after 72 hrsexposuretodrugs.

IntheCCRF-CEMleukemic cellline(Tables2and3 weobserved,atleastqualitatively, that the longer

the exposure time, the lower is the drugconcentration required to kill cells. In some cases, however, the

relationship between the cytotoxic potency and the exposure time is not linear, owing to summation of various contributions.

[Au(phen)C12]Cl exhibits a profile of cytotoxicity similar to that of cisplatin on the sensitive line,

although the actual concentrations that are needed to achieve the same effects are three times higher. Remarkably, [Au(phen)Cl2]CI largely overcomesresistance tocisplatin, so that it isat leastthree times more

effective thancisplatinitself onthe resistant line.

[Au(dien)CI]Cl2 is much less effective than [Au(phen)Cl2]Cl, on both cell lines, although their

time-dependentprofiles of cytotoxicityarequalitativelysimilar.

Both bipyridyl gold(Ill) complexes were shown to produce important cell killing effects on A2780,

SKOV3 and CCRF-CEM lines

(Table

4). The

_ICs0

values of8.8

_laM

and 3.3 gM for A2780 match those of

other gold(Ill) complexes, determined under identical conditions. In particular [Au(bipyC-H)(OH)][PF6]

qualifies asoneof the most activegold(Ill) complexeson the A2780 line. Lowerbut still important cytotoxic

effects were detected when both complexes were tested on the SKOV3 and CCRF-CEM cell lines.

Remarkablybothcompoundsareableto overcome toalargeextent resistancetocisplatin as witnessedbythe

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L. Messorietal. BioinorganicChem&try and Applications

Table 4

Inhibitory effectsofgold(Ill) complexesonthegrowthof somecisplatin-sensitive

(A2780/S, CCRF-CEM/S)and -resistant(A2780/R, SKOV3, CCRF-CEM/R)humantumorcell lines.

EDso*

(M) Cell lines A2780/S A2780/R SKOV3 CCRF-CEM/S CCRF-CEM/R [Au(bipy)(OH)2][PF6] 8.8+3.9 n=4 24.1+8.7 n=6 (2.7) 34.4+4.7 n=5 52.9+11.6 n=5 58.6+0.9 n=2 (1.) [Au(bipy-H)(OH)] [PF6] 3.3+1.4 n=5 8.2+1.5 n=7 (2.5) 13.3_+1.6 n=5 11.9_+2.1 n=5 51.2_+5.6 n=3 (4.3) Cisplatin 1.3_+0.2 11=5 15.3+1.9 n=5 (11.7) 21.6-+4.1 11=5 1.0+0.3 n=5 14.1-+8.2 n=2 (14.1)

*EDs0

is defined as the concentration ofdrug requiredto inhibit cellgrowth by 50%comparedtocontrol;( )

Ratio of

_EDso

of cisplatin-resistant cell line and

EDs0

of parental sensitive cell line; n number of

determinations.

Analysis ofthecytotoxicitydatapermitsformulationof some preliminarystructure/functionrelationships

that are summarized below:

i) the cytotoxicityof thesegold(Ill) complexesis associated tothepresence ofthegold(III)center(indeed

Au(en)2andAu(dien) aresignificantlymorecytotoxic thanthecorresponding platinumcompounds);

ii) thepresenceofhydrolysablechloridegroupson thegold(Ill)centeror,more ingeneral, ofgood leaving groups, doesnotrepresentan essentialrequirementforcytotoxicity;

iii) excessive stabilization of the gold(Ill)center results in loss ofbiological activity(Au(cyclam),with the

gold(Ill)centertightly boundto themacrocycle cage,is notcytotoxic,probablyasaconsequence ofits

lowreactivity).

iv) The amount ofgoldthat enters cells isroughly proportionalto theexposuretime, at leastduringthe first

hours. Thus, at least qualitatively, the longer the exposure time, the lower the drug concentration

requiredtokill cells.

Remarkably, most of the gold(Ill) compounds are able to overcome to a large extent resistance to

cisplatin as witnessed by the relatively low resistance index values, suggesting a different mechanism of

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Vol. 1,No. 2, 2003 Gold(Ill) Compounds"asNewFamily qJ’Anticancer

Drugs

MORE ADVANCED BIOLOGICALSTUDIESONCELLS:THECELLULAR EFFECTS OF TWO REPRESENTATIVEGOLD(Ill)COMPLEXES.

The cell growth inhibition assay represents the standard criterion for the screening of antitumor

compounds.

However;

this approach does not give direct information on the mechanism of action of the

individual drugs. Tobetter elucidatethe possible mechanisms through which cytotoxic gold(Ill) complexes

producetheirbiologicaleffects,additionalwork has beencarried outin ourlaboratoryonselectedtumorcell

lines. Experimentswere carried out onthe leukemic cellpopulationCCRF-CEM,either sensitive or resistant

to cisplatin, following treatment with two representative gold(Ill) complexes. Specifically, the effects of

Au(phen) and Au(dien) onthe above cell lines were monitoredbythe COMET assay [10,11], and by flow

cytometry studies [12]. This approach has resulted in a detailed description of cell responses to these

gold(Ill) complexes 13].

The single-cell gel electrophoresis assay (COMET assay) is an established method to reveal DNA

damageproducedbydrugsatthesingle-cell.level [11,12].Theelectrophoretic mobilityof alkalinedenatured

cellularDNAisretardedbycrosslinksthatare quantitatedasthe decrease in comet tailmoment,comparedto

H202-treated

controls. No clear relationship can be established between the DNA damage measured by COMETandthecytotoxic activity.Apossible explanationfor this lack of correlation is that thecytotoxicity

measured at a given time after drug exposure largely depends on the activity and the efficiency ofDNA

repair(excisionandpolymerizationphenomena,forexample). However,apartfrom difficulties in explaining somefeaturesof ourexperimentalresults,there is no doubt that the cometprofilesaredrasticallymodifiedby

both gold(Ill) complexes, thus providing unambiguous evidence for a direct interaction ofthese gold(Ill)

complexeswith DNA.

The flow cytometry results showthatboth gold(Ill) complexes modify thecell cycle lessmarkedly than

equitoxic amounts of cisplatin. The effectsinducedby gold(Ill)complexes on the sensitive lineare modest,

while transientbut significantmodificationsare observed in the resistant line. In spiteofthe modest effects

produced on the cell cycle, bothtested gold(Ill) complexes, butespeciallyAu(phen), were shown to induce

significantDNAfragmentation, suggestive ofinductionofapoptosis.

DNA ASAPOSSIBLETARGET FORGOLD(Ill)COMPLEXES: A BIOINORGANIC APPROACH

DNA isthe primary target forplatinum(ll) antitumor compounds and is the probable target for several

other antitumormetal complexes. Thus, we worked onthe hypothesisthat the cytotoxiceffects produced by

this group of gold(Ill) complexes on selected tumor cell lines might be a consequence of direct DNA damage; somesupportfor this view is offeredbythe above describedCOMET experiments.

The reactions of five gold(Ill) complexes- Au(en)2, Au(dien), Au(cyclam), Au(phen) and

Au(terpy)-with calfthymus DNA were analyzed in vitro through a number of classical physico-chemical methods

including spectrophotometry, circulardichroism, analysis ofDNAthermal denaturationprofiles anddialysis experiments [14]. Such investigations aimed at describing the gold(III)/DNA reaction in terms of’ DNA

structural modifications, strength and kinetic ofthe interaction, nature and reversibility ofgold(III)/DNA

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L. Messori etal. BioinorganicChemistryandApplications

We demonstratedthat the interactions ofthese gold(Ill) complexes with calfthymus DNA arerelatively

weak,reversibleand, in mostcases,electrostatic in nature. Given its chemical structure Au(cyclam) provides

the best example for a

"pure"

electrostatic interaction. The same holds for Au(en)2 thatprobably actsas a

groove binderby analogy with the isostructural Pt(en)2 complex; Au(dien) can form both electrostatic and

covalent bonds. For both Au(phen) and Au(terpy) intercalative binding is possible as well as formation of

coordinativebonds tonucleobases. Inallcases, binding iscompletelyreversible andgold(III) complexes are

displacedfromDNA by repeated ultrafiltrations.

The effects on DNAconformation produced bythe individual gold(III) complexeswerebest detectedby

circular dichroism(arepresentative experimentisshown inFigure4).

Fig. 4:

-4

200 250 300 350 400

;[nrn]

CD spectraofcalfthymus DNA (a)after addition ofAu(terpy)at the ratio r 0.1 (b),0.2 (c),0.5 (d),

Au(en)2 and Au(dien) at low concentrations were shown to induce few spectral modifications, while

largereffects were observed at higher concentrations still within the frame ofa B-type DNA conformation.

Au(cyclam)is more effective than the other polyamine complexes in inducingconformational modifications. The CD perturbations induced by Au(phen) and Au(terpy) are larger in agreement with an intercalative

binding model. On the basis of the spectrophotometric results mixed binding ofAu(terpy) to DNA-first

intercalation, thencoordination-maybehypothesized

Also the interactions of the bipyridyl compounds [Au(bipy)(OH)2][PF6] and [Au(bipyC-H)(OH)][PF6]

with DNAwereanalyzed in detailthroughthe sametechniques [6]. Itwasfoundthat the interactions with the

DNAdouble helix areweak,reversible andpredominantlyelectrostatic innature, suggestingthatDNA is not

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Vol. I, No. 2, 2003

Gold(llI)

Compounds’asNewFamily

_of

Anticancer

Drugs

CONCLUSIONS

The appreciable stability of these novel gold(Ill) complexes underphysiological conditions has allowed

extensive in vitro pharmacological testing. These compounds have been primarily characterized through in

vitro cytotoxictiy assays in line with thegeneral screening strategy ofNCI. Some preliminary correlations

between cytotoxicity andthe chemical structure havebeenproposed. Inviewofthe relevantcytotoxiceffects

exerted by most ofthe investigated complexes, more detailed studies have been performed to describe

cellular responsestothese substance. It isworthremindingthatpreliminary COMET results obtained in our

laboratory on Au(dien) and

Au(phen)

suggest thatboth complexes are capable ofproducing a direct DNA

damage.Occurrence ofadirect interactionof the present gold(Ill) complexeswith DNAis also supported by

CD and DNA melting experiments on

_calf

thymus DNA.

However,

the interactions ofgold(III) complexes with the DNA double helix are generally weak, reversible and predominantly electrostatic in nature, suggesting thatDNAis nottheprimary targetforthe cytotoxic effectsof thesecomplexes.

ACKNOWLEDGMENTS

This work was supported by a grant from "Ministero dell’Istruzione, dell’Universit/ e della Ricerca"

(Programmi di Ricerca Cofinanziati2001). Wethank thegroup ofProf. Mini (LaboratoryofPharmacology, UniversityofFlorence)forthesupportincarryingoutcytotoxicity experiments.

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