All-trans retinoic acid enhances gemcitabine cytotoxicity in human pancreatic cancer cell line AsPC-1 by up-regulating protein expression of deoxycytidine kinase

Hiroki Kuroda, Masanori Tachikawa, Yasuo Uchida, Koetsu Inoue, Hideo Ohtsuka, Sumio Ohtsuki, Michiaki Unno, Tetsuya Terasaki

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)116-121
Number of pages6
JournalEuropean Journal of Pharmaceutical Sciences
Volume103
DOIs
Publication statusPublished - 2017 May 30

Keywords

  • All-trans retinoic acid
  • Concomitant drug
  • Deoxycytidine kinase
  • Gemcitabine
  • Pancreatic cancer
  • Resistance

ASJC Scopus subject areas

  • Pharmaceutical Science

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