Reviews of Physiology, Biochemistry, and Pharmacology Volume 142 (Reviews of Physiology, Biochemistry, and Pharmacology)

188 Pages·2001·10.88 MB·English

by  J. Hofmann

241 .goloisyh~ y
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Editors
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stnetnoC
Modulation of Protein Kinase C in Antitumor Treatment
By .J Hofmann, Innsbruck, Austria
(With 4 Figures)
. . . . . . . . . . . . . . . . . . . . . . . . . . 1
Compartment-Specific Functions of the Ubiquitin-Protea-
some Pathway
By Th. Sommer, .E Jarosch and .U Lenk, Berlin, Germany
(With 2 Figures and 2 Tables) ................ 97
Transgenic Models of cz2-Adrenergic Receptor
Subtype Function
By .L Hein, Wiirzburg, Germany
(With 5 Figures) ...................... 161
Indexed in Current Contents
Modulation of Protein Kinase C
in Antitumor Treatment
J. Hofmann
Institute of Medical Chemistry and Biochemistry University of lnnsbruck
A-6020 Innsbruck Austria
Contents
1 Introduction ........................................................................................... 3
2 PKC in Cell Proliferation and Tumor Growth ..................................... 7
2.1 PKC Isoenzymes and Cell Proliferation ..................................... 7
2.2 PKC Expression in Tumor Cells and Tumors ............................ 11
2,3 Antiproliferative and Antitumor Effects of PKC-Modulation .. 16
2.3.1 Bryostatins ......................................................................... 16
2.3.2 Phospholipid Analogues .................................................. 19
2.3.3 Staurosporine-Derivatives ............................................... 20
2.3.4 Antisense Oligonucleotides ............................................. 22
2.3.5 Remarks and Conclusions ............................................... 24
3 PKC and Apoptosis ................................................................................ 25
3.1 Introduction .................................................................................. 25
3,2 PKC Activation Promotes Apoptosis .......................................... 25
3.3 PKC Activation Prevents Apoptosis ........................................... 26
3.4 PKC Inhibition Promotes Apoptosis .......................................... 27
3.5 PKC Inhibition Prevents Apoptosis ............................................ 29
3.6 PKC Isoenzymes and Apoptosis .................................................. 30
3.7 Remarks and Conclusions ........................................................... 35
4 PKC and MDR ........................................................................................ 38
4.1 Introduction .................................................................................. 38
4.2 PKC-Activity in MDR1-Mediated Drug Resistance ................... 38
4.3 Arguments Against a Role of PKC Activity in MDR ................. 39
4.4 PKC Inhibition or Downmodulation in MDR ............................ 40
4.5 Arguments Against a RoleofPKC Inhibition in MDR ............. 42
4.6 Phorbol Ester and MDR Modulation .......................................... 43
4.7 Results Indicating no Influence of Phorbol Esters
in MDR Modulation ..................................................................... 45
.J Hofmann
4.8 Influence of PGP Phosphorylation on MDR .............................. 46
4.9 Arguments Against an Involvement
of PGP Phosphorylation ............................................................... 48
4.10 Effects of PKC on the Levels of MDRI-mRNA and PGP ........... 48
4.11 Arguments against a Role of PKC on MDRI-mRNA
and PGP Levels ............................................................................. 49
4.12 The Role ofPKC Isoenzymes on MDR1-Mediated MDR .......... 50
4.13 Remarks and Conclusions ........................................................... 51
PKC Modulation in Drug Resistance not Mediated by MDR ............. 54
5.1 PKC Inhibiton Enhances the Sensitivity
to Antitumor Drugs ...................................................................... 54
5.2 PKC Activation Enhances the Sensitivity
to Antitumor Drugs ...................................................................... 57
5.3 PKC Isoenzymes in the Modulation
of Antiproliferative Activity ........................................................ 57
5.4 Remarks and Conclusions ........................................................... 58
6 Summary ............................................................................................... 59
References .................................................................(cid:127)..................(cid:127)..(cid:127)....... 60
Modulation of Treatment Antitumor in C Kinase Protein
1 Introduction
Protein kinase C (PKC) is a family of serine/threonine specific protein
kinases. The PKC isoenzymes can be classified into three groups: )i the con-
ventional (cPKCs) ,~c ~I, ,II~[ and y (require negatively charged phospholip-
ids, diacylglycerol or phorbol ester, and calcium for optimal activation), ii)
the novel (nPKCs) 8, ,~ 0, tl/L (mouse/human) and p (require negatively
charged phospholipids, diacylglycerol or phorbol ester, but no calcium), and
iii) the atypical (aPKCs) ~Jt (mouse/human) and ~ (do not require calcium,
diacylglycerol or phorbol ester, but only negatively charged phospholipids
for optimal activity) (Nishizulm, ;5991 Newton and Johnson, 1998). The PKC
isoenzymes (Fig. )1 are characterized by four conserved (C1-CA) and five
variable (VI-VS) domains (Stabel and Parker, Azzi 1991; et al., ;2991 Hug
and Sarre, ;3991 Stabel, 1994). The regulatory domain consists of the 1C and
the 2C region. CI contains the pseudosubstrate region that can inhibit the
enzyme by binding to the catalytic site (CA). In PKCp, the pseudosubstr.ate
domain is lacking. 1C also contains tandemly repeated cysteine-rich regions
to which DAG (diacylglycerol), phorbol esters and bryostatins can bind.
cPKCs and nPKCs contain two zinc fingers in thep horbol ester binding site,
aPKCs are characterized by a single zinc t'mger. 2C contains the calcium
binding region present only in cPKCs but not in nPKCs and aPKCs. Between
the 2C and the 3C region the so called hinge region is situated which serves
as cleavage site for calpain and trypsin during degradation. The 3C region is
believed to be the ATP binding site and the C4 region the catalytic site.
CKP isoenzymes seem to play an important role in activation of signal
transduction pathways leading to synaptic transmissions, the activation of
ion fluxes, secretion, proliferation, cell cycle control, differentiation or tu-
morigenesis. PKC has become of major interest as target for therapeutic
C4 3C
c ~
deteled ni ~) I C C2
deteled yltrap ni ,~ t deleted ni
8,0,~ G L, ,t t~
representation I. Schematic Fig. of kinase protein .C different the shows cartoon The
domains of CKP in the form inactive of the enzyme
.J Hofmann
ADRIAMYCIN ETOPOSIDE
ETOPOSIDE TENIPOSIDE
TEN IPOSIDE CAMPTOTHECIN
NITROGEN MUSTARD cis-PLATIN
cis-PLATIN NITROGEN MUSTARD ADRrAMYCIN
MMS 5-FLUOROURACIL MITOXANTRONE
VINBLASTINE VINBLASTINE DAUNOMYCIN
IRRADIATION IRRADIATION cis-PLATIN
/
x.e~, s,=, I .e,.2,o~.o
35p 35p .cym .sol $ar
PLK/72p 1 xab/2-I..'cb bctla~J
2MDM crs-v
MTA ~i~.C
EGR-I~ HYPOXIA- p=l~vAr / c-ju.
INDUCED Bk-FN
MULTICELLULAR I ACTIVATION OF
CONFLUENCE- REDUCED UNCOGENES
DEPENDENT. APOPTOSIS /
ADRIAMYCIN
ADRIAMYCIN DNA-REPAIR ~rmlv ETOPOSIDE
ETOPOSIDE Tepoisomera i
MITOXANTRONE TMGM .... / / \ INTRACELLULAR ....... TENIPOSIDE
CYCLOPHOSPHAMIDE 1HHLMh / ~. ~ DISTRIBUTION MDIATUONXOAMNYTCRIONN E
cis-PLATIN -- ~ hMS ^L. | ....... "~4~t~b:-.D~- M ~ 2P~M ~ ACTINOMYCIN D
p~,L jH.-.~M,.qBU.r..i.L. ...... S Mismatch UNAPolp ~'riapeR ~ . PJ'~070I ~ " MRP3. M IXI, ,PRL r..r, ,PRC8 ~ Hp. TAXOL
N/TRO, SOUREA HMG-domai'n ~ / X / VesicularrTranspott VINBLASTINE
%~i~'./ J,' .L 1ACRB ~ ~ Membrane noitazidiulF
IRRADIATION BRCA2 / ~ X VINCRISTINE
METHOTREXATE
T \ cis-PLATIN
INTRACELLULAR I \ T /AHLiI:/. ....
NOITAVITCA I DETATUM
INACTIVATION DECUDER UPTAKE DESSERPXEREVO
UNDEREXPRESSED
054-P ADRIAMYCIN
snienoihtollateM ETOPOSIDE esaremos;opoT I dna II
esarefsnarT-S-enoihtatulG TOPOTECAN edimar~c'y~o.cu4C es~hlnyS
D - ~.I :." h',.F ro a s t: cis-PLATIN alalidlmyhT esahtnyS
enidityC Deaminase elalofordyhiD esatcudeR
etalydrmyhT esahtnyS CYCLOPHOSPHAMIDE ediloolcunobiR esatcudeR
nicymoeiB esalordyH CHLORAMBUCIL etatrapsA esalymabracsnarT
MELPHALAN eninoihlemlysonedA-S esahlnyS
NITROGEN MUSTARD
ADRIAMYCIN ARA-C
ETOPOSIDE METHOTREXATE
cis-PLATIN VINCRISTINE ADRIAMYClN
RYCLOPHOSPHAMIDE ETOPOSIDE
MITOMYC~N C TENIPOSIDE
MELPHALAN TOPOTECAN
CHLORAMBUCIL AMSACRINE
5-FLUOROURACIL 5-FLUOROURACIL
AF','k-C MF THOTREXATE
3LEOMYCIN HvDROXYUREA
PALA
MDL 28,842
Fig. 2. Mechanisms causing resistance to antitumor treatment. ATM, ataxia telangi-
ectasia gene, (Westphal et al., 1998; Xu and Baltimore, 1996), bcl-2/bax (Farrow and
Brown, 1996, Zunino et al., 1997; Haq and Zanke, 1998), bcr/abl (McGahon et al.,
1994), BCRP, breast cancer resistance protein (Doyle et al., 1998; Ross et a/, 1999);
bleomycin hydrolase (EI-Deiry, 1997), BRCA1 (Husain et al., 1998; Chen et al., 1998),
BRCA2 (Chert et al., 1998; Chert et al., 1999), c-ab (White and Prives, 1999), c-jun
(Sanchez-Perez and Perona, 1999), cytidine deaminase (EI-Deiry, 1997), DNA poll,
DNA poymerase 31 (Ochs et al., 1999), dihydrofolate reductase (Schimke, 1986), DT-
diaphorase (Riley and Workman, 1992; Fitzsimmons et al., 1996; El-Deity, 1997),
EGR-1 (Ahmed et al, 1996), los (Niimi et al., 1991), glucosylceramide synthase
Modulation fo Protein esaniK C ni Antitumor tnemtaerT
intervention in a range of different diseases (Gescher et al., 1992; Bradshaw
et al., 1993; Basu 1993; Deacon et al., 1997; Nixon, 1997; Goekjian and
Jirousek, 1999). PKC may be involved in chronic granulomatous disease,
allergy, asthma, rheumatoid arthritis (Westmacott et al, 1991), transplanta-
tion (Woodley et al., 1991), AIDS (Kinter et al., 1990; Accornero et aL, 1998),
Alzheimer's disease (Chauhan et al., 1991), multiple sclerosis (Defranco,
1991), hypertension (El< et al., 1989), cardiac hypertrophy (Kwiatkowska-
Patzer and Domanska-Janik, 1991), atherosclerosis (Kariya et al., 1987),
diabetes (Inoguchi et al., 1992; Ishil et al., 1996) and cancer (Basu, 1993;
Blobe et al., 1994, Gescher, 1998). PKC is the intracellular receptor for tumor
promoting phorbol esters (Castagna et al., 1982; Niedel et al., 1983; Leach et
al., 1983). Short term exposure of intact cells with phorbol esters such as 12-
O-tetradecanoylphorbol-13-acetate (phorbol-12-myristate-13-acetate, TPA)
activates PKC, long term exposure down-regulates PKC activity. Phorbol
esters are able to promote tumor formation. Therefore, it was presumed that
noitavitca of PKC by TPA induces tumors and noitibihni may reduce -rac
sisenegonic or tibihni tumor growth. However, snoitagitsevni revealed taht
eht noitautis si more complicated. For example, nitatsoyrb ,I another PKC
(Lavie et al., 1997; Liu et al., 1999), glutathione-S-transferase (Ozols et al., 1990,
Tew,1994), heat shock (Ciocca et al., 1993); her-2/neu (Tsai et al., 1996), HMG-
domains (Huang et al., 1994), hMLH1 (De las Alas et al. 1997), hMSH2 (Aebi et al.,
.)6991 hypoxia (Bush et al., 1978; Vaupel et al., 1989; Sakata et al., 1991; H6ckel et al.,
1996), LRP, lung resistance-related protein (Scheffer et al., 1995), LDM 28,842, (Z)-
5'-fluoro-4",5"-didehydro-5"-deoxTadenosine (Dwivedi et al., 1999), mdm2 (Kondo
et al., 1995a), MDRI (luliano and Ling, 1976; Gottesman and Pastan, 1993), mem-
brane fluidization (Regev et al., 1999), metallothioneins (Kelley et al., 1988; Kaina et
al., 1990; Kondo et al., 1995b), MGMT, O6-methylguanine-DNA methyltransferase
(Erickson, 1991; Mattern et al., 1998), methyl methanesulfonate (MMS; Chen et al.,
1998), mismatch repair (Moreland et al., 1999, White and Prives, 1999), MRP, mul-
tidrug resistance-associated protein (Cole et al., 1994), MRP2 (Cui et al., 1999;
Hooijberg et al., 1999), MRP3 (Kool et al., 1999), multiceUular resistance
(Sutherland, 1988; Kobayashi et al., 1993; Pizao et al., 1993; Graham et al., 1994;
$tCroix et al., 1996), myc (Sklar and Prochownik, 1991), NF-,cB (Wang et al., 1999b),
P-450 (Doehmer et al., 1993), p53 (Lowe et al., 1993; Levine, 1997; Zunino et al., ;7991
Piovesan et al., 1998); p27/KIP (StCroix et al., 1996); p21/WAF1 twang and Walsh,
;6991 McDonald et al., 1996; Fan et al., 1997), pH (Martinez-Zaguilan et al, ;9991
Williams et al., 1999), ras (Scanlon et al., 1991; Isonishi et al., 1991; El-Deiry, 1997),
reduced uptake (Fry and Jackson, 1986; Perez et al., 1990; $1apak et al., 1990; Chu,
;4991 Ma et al., 1998a; Moscow, 1998; Ma et al., 1998b), repair (Masumoto et al.,
;9991 Chen et al., 1998; Husain et al., 1998, (:hen et al., 1999), ribonucleotide reduc-
tase ksAC et al, 1993; neY et al., 1994), thymidilate synthase (Kinsela et ,La 1997),
topoisomerase I and II (Yarbro, 1992; Robert and Larsen, 1998), vesicular transport
(Dietel et al., 1990), v-src (Masumoto et aL, 1999)
6 .J Hofmann
modulator with properties similar to those of TPA (Blurnberg, 1991; Ken-
nedy et al., 1992; Szallasi et aL, 1994) does not induce tumor formation. The
compound exhibits potent antitumor activity and is currently undergoing
phase I (Jayson et al., 1995, Grant et al., )8991 and phase II (Propper et al.,
1998) clinical evaluation as an anticancer drug.
In addition to be a direct target of antitumor treatment, PKC has been
shown to be involved in the resistance to anfitumor treatment and in the
modulation of apoptosis. Resistance to cancer chemotherapy is a major
PKC-
INHIBITORS
MILTEFOSINE
ILM
BRY
0
~0
l,l
).,,t
Z
CG
GF
DEXN
Fig. .3 Possible interactions between CKP and MDRl-mediated drug resistance.
Activation of CKP might activate the drug efflux by phosphorylation of PGP (A),
induce or activate proteins which modulate PGP ,B( Castro et al., 1999), or induce
the transcription and translation of MDRI-mRNA (C). Inhibitors of CKP might
prevent phosphorytation of PGP leading to a decrease the drug efflux (D), inhibit
the efflux of drugs by direct interaction with the drug binding site(s) or the ATP-
binding sites ofPGP (E), or prevent the expresosfiMoDnR I-mRNA (F)