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450 000 cancer cases diagnosed in Europe during 2012 1 700 000 deaths in Europe during 2012. Hsp90 overexpression is associated with oxidative stress and apoptosis. Oxidative stress is associated with increased levels of hsp90 in cancer cells.
450 000 cancer cases diagnosed in Europe during 2012 1 700 000 deaths in Europe during 2012. Hsp90 overexpression is associated with oxidative stress and apoptosis. Oxidative stress is associated with increased levels of hsp90 in cancer cells.
450 000 cancer cases diagnosed in Europe during 2012 1 700 000 deaths in Europe during 2012. Hsp90 overexpression is associated with oxidative stress and apoptosis. Oxidative stress is associated with increased levels of hsp90 in cancer cells.
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 $ $ H $H $ $
$H $ $ H $H $ H$ $H $
CH 3 $H $ CH 3 $ $ 2 $ 2 . $ 2 . $ 2 . %&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 )* 255+ *315! 0 25 50 75 100 125 'sc,-en ./atinib , - . / e r
o f
v i a / $ e
# e $ $ s 0 . $
1 2
o f
# t r $ 3 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 )* 255+ *315! 0 25 50 75 100 Ctrl 'sc,-en ./atinib 4 D H
$ e a 5 a % e
1 2 3 7n vitro 4+ 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