TY - JOUR
T1 - All-trans retinoic acid enhances gemcitabine cytotoxicity in human pancreatic cancer cell line AsPC-1 by up-regulating protein expression of deoxycytidine kinase
AU - Kuroda, Hiroki
AU - Tachikawa, Masanori
AU - Uchida, Yasuo
AU - Inoue, Koetsu
AU - Ohtsuka, Hideo
AU - Ohtsuki, Sumio
AU - Unno, Michiaki
AU - Terasaki, Tetsuya
N1 - Funding Information:
This study was supported in part by grants for the Revitalization Promotion Program (A-STEP) from the Japan Science and Technology Agency (JST) and the Uehara Foundation. We thank Dr. M. Tomi, Keio University, for supplying the genome DNA from JEG-3 cells. We also thank A. Niitomi, and N. Handa for secretarial assistance.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/5/30
Y1 - 2017/5/30
N2 - We previously showed that gemcitabine resistance in pancreatic cancer chemotherapy correlates with suppressed expression of deoxycytidine kinase (dCK), which catalyzes the rate-limiting step of gemcitabine activation. The purpose of the present study was to find a drug that might be useful to enhance the cytotoxicity of gemcitabine by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cell line AsPC-1. Screening of 40 prescription drugs identified 35 with no intrinsic cytotoxicity towards AsPC-1 cells. When AsPC-1 cells were pre-incubated with these drugs and then incubated with gemcitabine, we found that all-trans retinoic acid (ATRA) significantly decreased the viability by 28% compared with that of non-treated cells. Luciferase assay showed that ATRA transactivated the DCK promoter in AsPC-1 cells by about 2-fold compared with the untreated control, and an increase of dCK protein expression was confirmed by immunoblotting. ATRA decreased the half-maximal inhibitory concentration (IC50) of gemcitabine by 2.8-fold (ATRA-non-treated cells, 28.8 nM; ATRA-treated cells, 10.0 nM). The ATRA concentration of 0.03 μM was sufficient to enhance gemcitabine cytotoxicity, and the effect was well maintained in the concentration range from 0.03 to 50 μM. These results indicate that ATRA enhances gemcitabine cytotoxicity by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cells.
AB - We previously showed that gemcitabine resistance in pancreatic cancer chemotherapy correlates with suppressed expression of deoxycytidine kinase (dCK), which catalyzes the rate-limiting step of gemcitabine activation. The purpose of the present study was to find a drug that might be useful to enhance the cytotoxicity of gemcitabine by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cell line AsPC-1. Screening of 40 prescription drugs identified 35 with no intrinsic cytotoxicity towards AsPC-1 cells. When AsPC-1 cells were pre-incubated with these drugs and then incubated with gemcitabine, we found that all-trans retinoic acid (ATRA) significantly decreased the viability by 28% compared with that of non-treated cells. Luciferase assay showed that ATRA transactivated the DCK promoter in AsPC-1 cells by about 2-fold compared with the untreated control, and an increase of dCK protein expression was confirmed by immunoblotting. ATRA decreased the half-maximal inhibitory concentration (IC50) of gemcitabine by 2.8-fold (ATRA-non-treated cells, 28.8 nM; ATRA-treated cells, 10.0 nM). The ATRA concentration of 0.03 μM was sufficient to enhance gemcitabine cytotoxicity, and the effect was well maintained in the concentration range from 0.03 to 50 μM. These results indicate that ATRA enhances gemcitabine cytotoxicity by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cells.
KW - All-trans retinoic acid
KW - Concomitant drug
KW - Deoxycytidine kinase
KW - Gemcitabine
KW - Pancreatic cancer
KW - Resistance
UR - http://www.scopus.com/inward/record.url?scp=85013391669&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85013391669&partnerID=8YFLogxK
U2 - 10.1016/j.ejps.2017.02.021
DO - 10.1016/j.ejps.2017.02.021
M3 - Article
C2 - 28215943
AN - SCOPUS:85013391669
VL - 103
SP - 116
EP - 121
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
ER -
