Oxidative Stress and Hsp90 overexpression:

Between Defenses & Adaptation

Pedro Buc Calderon
Universit catholique de Louvain
Bruxelles-Belgique

3 450 000 cancer cases diagnosed in Europe during 2012

1 700 000 deaths in Europe during 2012

Ferlay et al., EJC 2013
(Hanahan and Weinberg, Cell 2011
(a) Hijacking a survival
pathway, i.e. Nrf2
(b) Protecting oncogenic
proteins, i.e. Hsp9
!ancer survival strategies"
Hanahan and Weinberg, 2000
da!ted "ro# Hanahan and Weinberg, 2000 and $ec%ers, 200&
Chaperone protein ( and
isoforms)

Very abundant protein (1-2% of

total protein content of the cell)

2-10 fold higher expression in

cancer cells

3 main domains ith specific

functions

!omo- or hetero-dimer

"nterest # re$uired in the

stabili%ation of many
oncoproteins& hile not
necessary for the biogenesis of
most polypeptides
Hsp9
#he Hsp9 chaperone
'he H(P)0 catal*tic c*cle
i+e+ Bcr-bl
$ec%ers, 2002
H$P9 inhibitors
!uinone redo" cycling as #$% generation
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%&i'ative stress by a (%$)generating syste*
+.) ,. -enites, .. (ojo, ,./. 0al'erra*a, 1. -lave, H. #aper, P. -uc !al'er2n. European Journal Medicinal Chemistry
34, +5+4)+5+6, 200,.
2.) ,. -enites, ,./. 0al'erra*a. H. #aper, P. -uc !al'er2n. Chemical & Pharmaceutical Bulletin 76(8), 8+7)8+9,
200)+
4.) ,. -enites, ,./. 0al'erra*a, 9. -ettega, (.!. Pe'rosa, P. -uc !al'er2n, ,. 0erra&. European Journal of Medicinal
Chemistry 37,(+2), 872)876, 20-0.
3.) ,. -enites, ,./. 0al'erra*a, H. #aper, P. -uc !al'er2n. Investigational New Drugs 29, 68)686, 20--+
7.) ,. 0erra&, (. -eck, N. :ejeans, !. ;lorieu&, -. $i', (.!. Pe'rosa, ,. -enites, :. 0<s=ue>, ,./. 0al'erra*a, P. -uc
!al'er2n. nticancer gents in Medicinal Chemistry ++(2), 2+4)22+, 20--.
8.) ,. -enites, ?. ;utierre>, ,. .2pe>, @. (ojas, .. (ojo, @. !osta, @.P. 0inar'ell, P. -uc !al'er2n. Natural Product
Communications 6(7), 8++)8+3, 20-2.
6.) @.( 9viecinski, (.!. Pe'rosa, 9.-. Aelipe, @. Aarias, !. ;lorieu&, @. 0alen>uelaB -. $i'B ,. -enitesB ,./
0al'erra*aB ,. 0erra&B P. -uc !al'er2n. Biochemical and Biophysical !esearch Communications 32+, 285)264,
20-2+
5.) A. -ravo, !. !ont>en, ,. @ollo, P. -uc !al'er2n, ,. -enites. Journal of "he Chilean Chemical #ociety 76(4),
+274)+277, 20-2.
9.) :. (Cos, ,. -enites, ,./. 0al'erra*a, @. Aarias, (.!. Pe'rosa, P. -uc !al'er2n, ,. 0erra&. Current "opics in
Medicinal Chemistry +2, 293)2+2, 20-2.
+.) 9.-. Aelipe, ,. -enites, !. ;lorieu&, -. $i', @. 0alen>uela, @.(. 9viecinski, (.!. Pe'rosa, ,./. 0al'erra*a, Ph.
.evD=ue, -. ;alle>, ,. 0erra&, P. -uc !al'er2n. Biochemical and Biophysical !esearch Communications 344, 764)
765, 20-..
++.) A. -ravo, !. Ea*bra, 9. 0enegas, :. (Cos, P. -uc !al'er2n, ,. -enites. Journal of "he Chilean Chemical #ociety
75(2), +644)+648, 20-..
+2.) ,. -enites, .. -ustos, :. (ios, A. -ravo, ,. .2pe>, $. ;ajar'o, .. (ojo,

P. -uc !al'eron. Blacpma +2(3), 3+4)3+9,
20-.+
+4.) P. /renas, /. PeFa, :. (Cos, ,. -enites, ;.;. @uccioli, P. -uc !al'er2n, ,./. 0al'erra*a. Molecules +5, 95+5)
9542, 20-.+
+3.) ,. -enites, 0. #ello, N. Alores, :. #apia, ,. .2pe>, :. (Cos, P. -uc !al'er2n. Blacpma +4(4), 296)43, 20-/.
+7.) @. Aarias, !.#. Pich, N. -ucker, 9.-. Aelipe, @.(. 9viecinski, A. 'a $ilva, #. ;Gnter, :. (Cos, ,. -enites, ,./.
0al'erra*a, P. -uc !al'er2n, (.!. Pe'rosa. Molecular Medicine !eports +(+), 37)3+, 20-/.
+8.) A. -ravo, (. Hlloa, 9. 0enegas, @.!. !ont>en, :. (ios, @. -riceFo, P. -uc !al'er2n, ,. -enites. Journal of "he
Chilean Chemical #ociety$ in press 20-/ .
0122 cells
#he o&i'ative cleavage of Hsp9
'u#or
sensitivit* 3
but not onl* in 0122 cells44
'riefly& hsp(0 clea)age
is time-dependent&
is independent of any protease&
is induced by a *enton-type reaction&
is pre)ented by antioxidants&
it occurs at +-terminus&
it seems to be specific,,
-eck et al, 29
&
C
Hsp90
&ucleotide binding site
'
d
(
(
(
)
*
)
*
)

F
e
2
+
/scI@en
H
2
%
2
$H

@echanis* of o&i'ative cleavage

!131
"132
#$eava%e site &
'130
(133
-eck et al, 2+2
-iological relevance J
K562: chronic myeloid leukemia cell line expressing Bcr-Abl

'cr--bl #

*usion protein resulting from a translocation (Ch (

and 22 . /hiladelphia Chromosome 0)

-berrant tyrosine 1inase responsible for the

transformation of normal cells into malignant cells

"ts inhibitor "matinib mesylate and deri)ati)es

represent the best treatment for C23 although
resistances do appear
Ba".5Bcr-bl W'
Ba".5Bcr-bl 62110
Ba".5Bcr-bl '.-17
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1. Cell proliferation
Khat about cells e&pressing *utate'
for*s of -cr)/bl J
7n vivo 4+
Hsing -aA4 cells
bearing *utate'
-cr)/bl)#4+71
-albIc nu'e *ice were injecte' s.c. with + *illion of -aA4I-cr)/bl)#4+71 cells. 5 'ays after,
*ice were treate' either with ascI*en (+ g per kgI+ *g per kg) or with saline every other 'ay.
-eck et al, 2++
'a%e ho#e #essage8
-
!ancer cell redox ho#eostasis represents a specific
vulnerability that can be selectively targete' by re'o&
*o'ulators.
- (e'o& cycling o&i'ative stress (H
2
%
2
), lea's to Hs!)0
cleavage that appears to be selective of cancer cells,
suggesting potential clinical applications
Khat about cells e&pressing *utate' for*s of -cr)/bl J
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Adapted from Gomez-Mejiba et al., Free Radic Biol Med, 2009
D'6O 7
-eck et al, 2+2
9reen:control
;ed:treated
<ello=:both
Hs!)0
Cleaved Hs!)0
Hi%8$i%8ted: tr9pti# peptides 0 :nder$ined: #89.otr9pti# peptides
'he Bergerat "old >-))&?
-.0 -/0
@7(A79BC9D9C<(<LD60DD : hs!)0
>Prodro#ou et al, Cell )08 21, -))&?
hsp9
Cancer
$urgery
(a'iotherapy
New 'rugsI
treat*ents
$tan'ar'
!he*otherapy"
/nti*etabolites
/lkylants
Hor*onotherapy
/ntibiotics
L..
/nthracyclines
/nsa*ycines
ntrac*clines structures and #echanis# o" action
daunorubicine doxorubicine e!irubicine idarubicine
ntrac*clines and P-gl*co!rotein8
$a*e syste* for bacteria an' tu*or cells