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