dr. yusuf baran · dr. yusuf baran abdullah gul university faculty of life and natural sciences...
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Dr. Yusuf BARAN
Abdullah Gul University
Faculty of Life and Natural Sciences
Molecular Biology and Genetics
www.yusufbaran.net
ybaran@gmail.com
Ist International Conference of TWAS Young Affiliates Network
22-14 August 2017 Rio De Janerio, Brasil
İzmir Institute of Technology
Faculty of Science
Molecular Biology and Genetics
Patients with the same diseasePatients with the same disease
Good response to
Treatment
No response to
Treatment
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
0
20
40
60
80
100
120
30 100 1000 10000 100000
VCR (nM, 48 hr)
% A
bso
rban
ce
in M
TT
0
20
40
60
80
100
120
0,001 0,01 0,1 1 10 100
Ara-C (nM, 48 hr)
% A
bso
rban
ce in
MT
T
Baran Y. et al.
Experimental Oncology 2006 28(2):163-165.
HL60 :4 nMHL60/VCR :300 nM
HL60 :0.12 nM HL60/VCR : 5 nM
HL60 4 nM
HL60/VINC 300 nM
Baran Y et al.
Hematology, 2007 12(6);511-517.
HL60 62 nM
HL60/DOX 666 nM
0
50
100
150
200
250
300
350
400
450
500
Control HL60/DOX-220
No
rmilis
ed
to
Beta
Mic
rog
lob
ulin
MRP1
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
BCR-ABL
Baran Y. Et alJournal of Biological
Chemistry, 2007 282(15); 10922-10934.
Bcr-Abl
Beta aktin
Bcr-Abl
Beta aktin
K562 /IMA-0.2 /IMA-1
Baran Y. Et alHematology, 2007 12(6);497-503.
MEG-01 /IMA-0.2 /IMA-1
Baran Y. Et. al.Leukemia and Lymphoma, 2013; 54(6): 1279-1287.
Bcr-Abl
Beta actin
K562 K562/NIL-50
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
0
20
40
60
80
100
G1 G2 S Apoptosis
Cell cycle (48 hr)
% C
ell p
op
ula
tio
n Control
500 nM IMA
K562
Hücre
Popula
syon Y
üzdesi
Hücre Döngüsü (48 s)
0
20
40
60
80
G1 G2 S Apoptosis
Cell cycle (48 hr)
% C
ell p
op
ula
tio
n Control
500 nM IMA
K562/IMA-0.2
Hücre
Po
pu
lasyo
n Y
üzd
esi
Hücre Döngüsü (48 s)
Baran Y. Et al.Journal of Biological Chemistry2007 282(15); 10922-10934.
Baran Y. Et alHematology, 2007 12(6);497-503.
Bcl-2
Bcl-XL
Bax
ß Aktin
1 2
1- K562/IMA-1 µM2- K562
MEG/01-IMA-1 MEG-01
Baran Y. Et al Journal of Biological Chemistry, 2007 282(15); 10922-10934.
Baran Y. Et alHematology, 2007 12(6);497-503.
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
Baran YInternational Journal of Cancer2010 Oct 1;127(7):1497-506.
0
1000
2000
3000
4000
C-18:1-
Cer
C14-Cer C16-Cer C18-Cer C20-Cer C24-Cer C24:1-Cer
% C
han
ges
cer
amid
e le
vels
K562
K562 + 500 nM IMA
K562/IMA-0.2
K562/IMA-0.2 + 500 nM IMA
Baran Y. Et al Journal of Biological Chemistry, 2007 282(15); 10922-10934.
0
0,4
0,8
1,2
1,6
Vector hLASS1 hLASS2 hLASS5 hLASS6
Rel
ativ
e ch
ang
es in
Cyt
op
lasm
ic/m
on
om
eric
JC
-1
Control
500 nM
CerS2, -5 and -6
CerS1
Beta-actin
Baran Y. Et al Journal of Biological Chemistry, 2007 282(15); 10922-10934.
Vector CerS1 CerS2 CerS5 CerS6
Baran YInternational Journal of Cancer2010 Oct 1;127(7):1497-506.
0
0,1
0,2
0,3
0,4
0,5
0,6
S1P
S1P
leve
ls (
pmol
/nm
ol P
i)
K562
K562 + 500 nM IMA
K562/IMA-1
K562/IMA-1 + 500 nM
0
50
100
150
200
Cell lines
% E
nd
og
en
ou
s S
K a
cti
vit
y
K562
K562 + 500 nM IMA
K562/IMA-1
K562/IMA-1 + 500 nM IMA
0
1
2
3
4
0,5 1
Imatinib (µM, 48 hr)
Fo
ld c
han
ges in
Try
pan
blu
e p
osit
ive c
ells Scr RNAi
SK1 RNAiK562/IMA-1
SK-1
Beta actin
0
5
10
15
Vector SK1
Rela
tive C
han
ges in
casp
ase-3
acti
vit
y
Control
1 µM IMA
K562
SK-1
Beta actin
Baran Y. Et al Journal of Biological Chemistry,2007 282(15); 10922-10934.
Baran Y. Et al Journal of Biological Chemistry, 2007, 282(15); 10922-10934.
SK-1
Beta actin
Salas et al. Blood, 2011, 117(22):5941-52.
Salas et al. Blood, 2011, 117(22):5941-52.
Salas et al. Blood, 2011, 117(22):5941-52.
Salas et al. Blood, 2011, 117(22):5941-52.
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
2
K562 K562/IMA-1
Fo
ld C
han
ges i
n E
xp
ressio
n l
ev
el
of
GC
S
*
* p<0.01
1 2 3 4 5 6
B
Baran Y. Et al Journal of Cancer Research
and Clinical Oncology,2011, 137(10):1535-1544.
0
20
40
60
80
100
120
Control 0.2 0.5 1 2 5
Imatinib (µM, 72 hr)
% A
bs
orb
an
ce
in
MT
T
K562/IMA-1 + PDMP (20 µM)
K562/IMA-1 + PDMP (20 µM) + IMA
K562/IMA-1K562/IMA-1 + PDMP
Baran Y. Et al Journal of Cancer Research
and Clinical Oncology,2011, 137(10):1535-1544.
Patient No Case
1 Newly Diagnosed
2 Positive response to Nilotinib
3 Newly Diagnosed
4Loss of Molecular response
5 Newly DiagnosedCooking!
Patient No Case
1 Newly Diagnosed
2 Positive response to Nilotinib
3 Newly Diagnosed
4Loss of Molecular response
5 Newly DiagnosedCooking!
Patient No Case
1 Newly Diagnosed
2 Positive response to Nilotinib
3 Newly Diagnosed
4Loss of Molecular response
5 Newly DiagnosedCooking!
1 9,350218
3 10,48315
4 14,37012
5 12,295
Patient No Case
1 Newly Diagnosed
2 Positive response to Nilotinib
3 Newly Diagnosed
4Loss of Molecular response
5 Newly DiagnosedCooking!
Patient No Case
1 Newly Diagnosed
2 Positive response to Nilotinib
3 Newly Diagnosed
4Loss of Molecular response
5 Newly DiagnosedCooking!
Cooking!
Cooking!
Cooking!
Mechanisms of resistance to anti-cancer drugs
Decreases in intracellular concentrations of anticancer agentsresulting from increased efflux or decreased influx
Alterations in drug target
Increases in drug targets or removel of drug targets
Changes in expression levels of apoptotic and antiapoptotic genes
Aberrations in ceramide metabolizm
Increases in DNA repair
Epigenetic differences
MicroRNAs
İzmir Institute of Technology & Abdullah Gul University
Thank You...Yusuf BARAN, 2015
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