TY - JOUR
T1 - SIRT1 inhibition in pancreatic cancer models
T2 - Contrasting effects in vitro and in vivo
AU - Oon, Chern Ein
AU - Strell, Carina
AU - Yeong, Keng Yoon
AU - Östman, Arne
AU - Prakash, Jai
N1 - Funding Information:
The authors thank Anna-Karin Persson and Kenth Andersson for excellent technical assistance with animal work. We also extend our gratitude to Professor Lars-Gunnar Larsson for useful advice on senescence. C.E.O was supported by USM , Malaysia short term Grant 304/CIPPM/6312135 and FRGS Grant 203/CIPPM/6711335 . J.P. was funded by Swedish Research Council young researcher project grant ( 621-2011-5389 ). K.Y.Y was supported by the Ministry of Education (Malaysia) , Malaysia MYBRAIN15 scholarship.
Funding Information:
C.E.O was supported by Universiti Sains Malaysia Short Term Grant (304/CIPPM/6312135) and Fundamental Research Grant Scheme (FRGS) Malaysia (203/CIPPM/6711335). J.P was funded by Swedish Research Council young researcher project grant (621-2011-5389). The funders played no role in study design, data analysis or preparation of the manuscript.
Publisher Copyright:
© 2015 Elsevier B.V.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/6/15
Y1 - 2015/6/15
N2 - Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
AB - Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H-Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527.
KW - EX527
KW - Gemcitabine
KW - Pancreatic cancer
KW - SIRT1
KW - Sirtuin
KW - Tumour resistance
UR - http://www.scopus.com/inward/record.url?scp=84927143064&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2015.03.064
DO - 10.1016/j.ejphar.2015.03.064
M3 - Article
C2 - 25843411
AN - SCOPUS:84927143064
SN - 0014-2999
VL - 757
SP - 59
EP - 67
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -