The chemokine receptors CCR5 and CXCR4 serve as co-receptors for the human immunodeficiency virus 1 (HIV-1) and thus, are important cellular components during HIV-1 cell entry. In recent years, a new biological role for chemokine receptors has emerged in assisting the spread of primary tumors to distant secondary sites within the human body (metastasis). This review highlights some of the HIV-1 cell entry inhibitors (antagonists), which are currently in development and/or under evaluation in clinical trials, and discusses the therapeutic use of these new antagonists for the treatment of certain forms of metastatic cancer

Bachmann, Andre S

Gamper, Ivonne

eVols at University of Hawaii at Manoa

CANCER RESEARCH CENTER HOTLINE kLPW%1ICARE WIl HE EM OG1 I MD PHD CONTRIBUTING I DITORJ(JIJRNI!iiLKilling Two Birds with One Drug: A New Application for HIV-iCell Entry Inhibitors in the Treatment of Metastatic CancerAbstractThe chemokine recpotors CCR5 and CXCR4 serve as co-receptors for tfe human immunodehdiency v/run 1 (H/V-i) and thus, areimportant cellular components during HIV- 1 cell entry In recentyears, a new b/c/op/cal role for chemokine receptors has emergedin assisting the spread of primary tumors to distant secondary siteswithin the human body (metastasis). This review highlights some ofthe H/V-i cell entry inhibitors (antagonists), which are currently indevelopment and/or under evaluation in clinical trials, and discussesthe therapeutic use of these new antagonists for the treatment ofcertain forms of metasta tic cancerChemokines and chemokine receptorsThe chemokines belong to a large family of small, chemotacticcytokines. which play an important role in mediating inflammatory responses, leukocyte homing, and cell migration (chemotaxis)in specific types of leukocytes. Chemokines are divided into foursuhfamilies (CC. CXC, C, and CX3C) characterized by a distinctpattern of conserved cysteine residues°2. Chemokines mediatetheir biological effects by binding to chemokine receptors. a family of seven transmembrane (7TM) receptors. which belong to theG protein-coupled receptor (GPCR) superfamily (Figure 1). Thechemokine receptor family is divided into two main subclasses,which consists of eleven CC (CCR I-Il) and six CXC receptors(CXCRI-6). and also includes lymphotactin receptor XCRI andthe fractaline receptor CX3CRl’. The binding of chemokines(agonists) to the receptor triggers a series of intracellular eventsmediated by heterotrimeric G proteins, which ultimately leads toactin polymerization and chemotaxis (Figure 1 )/The role of chemokine receptors in HIV-1 cellentryThe human immunodeticiencv virus 1 (l-llV— 1) enters its host cell bysequential interaction with receptor CD4 and one of the chemokinereceptors! HIV- I co-receptors CCR5 orCXCR4 (Figure 1 Y”/ WhileR5-tropic HIV- I strains initiate infection through interaction withCCR5 and predominate during the period of’ clinical latency. themore virulent CXCR4-interacting X4-tropic H IV- I strains are foundlate in infection and after AIDS symptoms appearh However, manyprimary clinical isolates are dual—tropic and can use either CCR5 orCXCR4 to infect the host cellsh Although many other chemokinereceptor subsets also have HIV- I co-receproractivity in vitm. a function in v/co has primarily been demonstrated for CCR5 and CXCR4,Most impressively, a clear role for CCR5 in HIV— 1 pathogenesis hasbeen found through the discovery of a naturally occurring. 32—hpAndré S Bachmann PhD, Assistant Professor’Natural Products and cancer Biology Programcancer Research center of Hawaii,and Ivonne Gamper MS, Graduate Student*corresponding Author: abachmann@crch.hawaii.edudeletion mutant in the human CCR5 gene (CCR5A32) that rendershomozygotes highly resistant to HIV— I infection’.ExtracellularspacePlasmamembraneIntracellularspaceAntagonistsHIV-1 ChemokinesI/Chemokine CReceptor(eg. CCRS, CXCR4)i4rC hem ota xis‘—S EQ ‘ ec C anrar’ c”cw i’g :ne p”oocsac e;s tra’a mcrane-spa” rc tccoa’ac1c a c”e”c”a ‘ecectc’ c’ ce3”o3 c’o:e’ cccc’ec ‘ceo:o’ GCR cjp”am T’ a chr’cvnesa— ‘ala cams of rnOK ‘cecto’s ac oa,oa “Mce“c: rcjQfl ‘‘a —alec” ‘e” c 3 Dmters ‘ S.D..1T” s t. Ornate ‘rag :c cc:’ cc ‘r’”.za: c” .:“c cc im’.c” cher’o‘aAs Tc”L”c “‘-ode’•oec,.’’s’ -\‘‘ :I:’scsDra‘ecec:c’ CC5 a”a CXOR os cc.raceo:c’s. acm ,‘,‘:r :‘e a“cxc’ CD :c “:‘ :‘v a’ce: Opi Ti ‘acm: y ama mac —“I‘eceo’c ai:agc’ :s cc c -Vc crc.‘o”sc’ccF1”ok,’.’c.tjcm “a,yo”c’a’””,’—ca“s:ac:a:,’; :,r”c”s C c’ac?v-: “‘‘N A” ro-ti ‘i220Development of new Hay-I cell entryinhibitorsThe recognition that chemokine receptors junctionas co—receptors and assist the cell entry of l-HV- Ifueled the interest in this family of receptor proteins.which resulted in a significant increase in publishedliterature after 1995 (Figure 2). The exploration olchemokine receptors as potential therapeutic targetsfollowed soon after and led to the development ota number of HIV-l cell entry inhibitors (e.g. TAK779 and AMD3 100) and derivatives leg. TAK-22(tand .—\MD070, which are currently in developmentor entering clinical phase trials (Table I) . Fhcentagnit peciticall block the binding of the 1IIV-ens elope protein tEns to either C’( kS or (‘XCR4and thLis lorm a new generation of anti-HIV drug’.ss hieh may be used in combination with existingpro1eae and reverse—traosenp[a’e RT inhihitor totreat HIV- I infoction A number ol phannaceuticalcompanies are leading in the discovers ol cell entrinhibitors, including Schering Plough. (laxo SmithKline. Pfi,’er. Millennium. Merck. Takeda. \o arti.and Astra /eneea.Table I Represeni five exam s of CCR5 and CXCR4 antagontstsClinicalReceptor Antagonist Triah CommentsCCR5 TA10779 Phase First non-peptidic inhibitor, discontnuedTAK-220 Phase Derivative of TAK-779, orally bioavaiiabieSCHC Phase Also called SCH 351125. orally hioavalable. discontinuedSCH-D Phase Ii More potent in vitro than SCH-C, orals OioavaiiabieAD1 01 NA Also called SCH 350581 overiappino b:ndings sites wif.h SCHC8913 NA Inhibits multidrugresistant HIOl orals Oaavai.abieCMPD f 57 NA Also called MRRf effective :n SlVE:nfec.1ed rhesus m.acaauesGW873140 Phase S Orally bi.oavalabieiJi<.4278.57 Phase lOll Derha.iive ci UK177543, oral5 cc•.avalabOCXC0:” Ar,n’”r P’asv SIrSAM.311’l S—aye ii Deroai.v ci AM[)3 77. “cliv s:ecAi7D205 N A Deria:’,e ciKFHr930 NA And HO Doi:e 5”:l’c.At,1D’_7Riven-c c Ce Cyroc 2775: Hork 2003-1 and R.Oeac S Hoc” 2775S-nec! oeceiopme1 mane accorong I0 oaosnec I!eraLre ancc aseoved ‘‘c”rnl.c” on IreNA. ‘tc’rn-aicn on cuiren! ce’e-conrenr cage cci avalage 0’ macs ,inciearnumber of published articles in PubMed inttp www nco’.nlrn nih.govi from 1988 to 2004 using the seaiuiCXCR4”. The number ot published artices increased ‘apidly after the discovery that CCR5 and OXCR4nombor of articles re ects the PuoMed “esults obtained wth the indicated search terms on y.articles, Other symbo s sjcn as us’n or GXGR c OKR5 for CCR5) were not incuded asA role for chemokine receptors incancer metastasisIn many cancers, metastasis is the leading cause ofmortality. Despite extensive research. Ihe precisemechanisms h which cancer cells are disseminatedto sites distant from the primary tumor are not fullyunderstood, While the chemokine-mcdiated cell migration of leukoc tes has lone been known, it hasonly recently been found that tumor cells may utilizesimilar mechanisms during cancer meiastasis. It hasbeen proposed that subsets of chcmokine receptorsare expressed b certain tumor cells and that specificchemokines are highly expressed at sites of cancermetastasis, thus su!eestin that speci tic combinationsf chemokines and chcmokine receptors determinethe final destination of nietactanc tumor cellsThis concept i’ supported b several reports. whichdescribe the expression of a distinct non—randompattern of subsets of functionally active chemokinereceptors, such as CXCR3 and C’XCR4 in humanmelanomaceHs5°,CXCR4 in metastatic breast cancercells, and CCR7 and CCR 10 in skin metastases.Other evidence for the role of chemokine receptorsin cancer metastasis include the findings that CCR5i’ expressed on stronial cells and thereh promotespulnionar metastasis and that the upreulation ofC\CR4 is essential for HER2—mediated breast tumorinetastasis. Moreover. the relevance of cheniokinereceptors in 1110 was demonstrated li usine CX(’R4—specific antihodics. which significantly reduced theFigJ”e 3.— Human neurobias:oma NB) cells express endogenous XOR4 B. 0. Fl. but not CCR5 A. C. El. LAN1. NMB-7. and SK-N-SH cci s wee incubated wth OXOR4 or CCR5-recogriz ng primary moroclona antibodies andFlTc- aneled secondary antioody or secondary antibody alone as a contro’. Cell surface stained ccl s were measuredby flow cytonletry (FACScam and data were evaluated using the program eliQuest. NB cells were cultured as previousy descibed222formation of lymph node and lung metastases in immunodehcientmice and by stud ing CCR5 knockout juice ((‘CR51. ‘ hichdeveloped fewer metastasesExpression of chemokine receptor CXCR4 inhuman neuroblastoma cellsThe expression of cheniokine receptors was initially thought to herestricted to leukocvtes However, there is now clear evidence thatthey are also expressed in neurons’ as well as neuroblastoma (NB)tumors2125.NB is a pediatric cancer, in which malignant cells formin the nerve tissue of the adrenal gland. neck. chest, or spinal cord.Metastatic dissemination of L3 occurs hr hemogenous and lymphatic pathways to F mph nudes, hone. and hone marrow. Recentstudies reported the presence of endogenous (‘XCR4 in NB cells-and our own data sviih three human NB cell lines confirmed theirobser alions Figure 3. In contrast. ‘s e did not detect any CCR5protein in thesecells. which is in accordance with previously reportedfindings using the NB cell line SH—SY5Y. a suhclone ofSK—N-SH-’.A biological role for CXC’R4 in the development of bone marrowmetastases was proposed. thus further underlining the importanceof CXCR424Potential application of HIV-1 cell entry inhibitors as anti-metastatic drugsThe recognition that CCR5 and CXCR4 play a crucial role in certainforms of cancer metastasis clearly suggests that HIV— I cell entrrinhibitors, which are generally safe and well tolerated in HIV— Ipatients, should be exploited in clinical cancer trials. These anti—metastatic drugs ma’s act in several ‘s’sar 5: hr preventing the metastaticspread of primary tumor cells. h\ inhibiting macruphage infiltrates.and by induction of chemukine receptor—mediated tumor cell arrestand programmed cell death tapoptosis)’’’. In gain more insightsinto the role of CXCR—I my laboratory is interested in exploring theefiects ofHJV— I cell entr inhibitors on the migration, differentiation.and apoptosis of human NB eel Is with the ultimate goal to developnovel therapeutics for high-risk NB patients.ConclusionsIt is intriguing to speci late that HIV— I cell entry inhibitors couldpro’s e to he useful therapeutics fur the prevention and treatment ofmetastasis of (‘CR5— or CXC’R4—associated tumors. Furthermore,the development of antagonists that speciticallx block the functionof other chemokine receptors will further contribute to formulatingselective anti—metastatic therapies. whic Ii are likely to reduce unwanted side effects in patients. i’he screening of a larger number ofcancer patients Will be necessary to better define the expression pattern of chemokine receptors in metastatic tumors. Such information,combined with an effort to determine a cancer patient’s individualchemokine receptor profile prior to treatment, will allow a more per—sonalized patient care with improved therapeutic outcome. Finally.chemokines are also with a number of autoinflammatorrdiseases including multiple sclerosis, rheumatoid arthritis, diabetes.and endometriosic, further stiggestin a wide range of therapeuticippI icatiuns for ehemokine receptor antagonists - -‘r ua ‘re in formal ion abs ut the ( (ancer Research Center of 1—1 ass ai i -inlease ‘sisit our ‘svebsite at ‘sv’svw,crch,ore.AcknowledgmentsThe author would like to thank Dr. Bonnie J. Warn-Cramer. Dr. Patricia S. Lorenzo.and Mr Ctaig S. Coleman (Cancer Research Center of Hawaii) for theircrilical reviewof the manuscript. The National Institutes of Health AIDS Research and ReferenceReagent Program kindly provIded the monoclonal CCR5 and CXCR4 antibodies. Ms.lvonne Gamper was a graduate student in the laboratory of Dr. André S. 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(2005) Oncogene In Press,Surfe.’s Medical Association: Conference in Biarritz, FranceThe f/nsa Eu’orear rr.eetlna of twa SMA nW be held 0omSetemCser 30 o ‘Dc5ccer 9, 2005 The oonference mcci toe ‘:1to cn,’s:o.vInS (InCa flea’ -c.im Oro:eSs:OrCun ‘,‘.‘ro:ns )42:t:C”t( ‘cnd;or .,‘.,‘h .me nofers 9Tfl5ei JEan.The conferensoe orogram mU) (nch:,J.de presentatons by a))affendees to uc:date the status of the hea(ih-care/surhna interface plus networking w(th internatiorsa) colleagues. Additionaldetayr are o a blnr or he M.Th eL (C4 Sc waamoon wa ) Fth.e events sectio.n.The conference registration fee of $2,200 gOD includes oneoceanfront room (based on doub(e oocuoancy) for ten n)hts..three meals. her day and ground transoc.rt e’ach day to s,cr.i,u.:lt,,ed surf snots.223

Killing two birds with one drug: a new application for HIV-1 cell entry inhibitors in the treatment of metastatic cancer.

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Killing two birds with one drug: a new application for HIV-1 cell entry inhibitors in the treatment of metastatic cancer.

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