KNK437 downregulates heat shock protein 27 of pancreatic cancer cells and enhances the cytotoxic effect of gemcitabine.
BACKGROUND
Our previous proteomic study demonstrated that expression of heat shock protein 27 (HSP27) is upregulated in gemcitabine (GEM)-resistant pancreatic cancer cells and that it suppressed the cytotoxic effect of GEM on the cells. This report describes the benefits of a treatment strategy combining the HSP inhibitor KNK437 with GEM for GEM-resistant pancreatic cancer cells.


METHODS
We used 2 human pancreatic cancer cell lines, GEM-sensitive KLM1 and GEM-resistant KLM1-R. KLM1-R was treated with KNK437, and we examined the expression of HSP27 by Western blotting. The cytotoxicity of GEM and KNK437 for KLM1-R was investigated by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay.


RESULTS
The expression of HSP27 in KLM1-R was dramatically reduced by KNK437. In addition, the in vitro antitumor cytotoxic effect of GEM on KLM1-R was enhanced by combination treatment with KNK437 compared to GEM alone.


CONCLUSIONS
This study supports the potential therapeutic benefits of a treatment strategy combining KNK437 with GEM.
Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Kumiko
K
Taba
Yasuhiro
Y
Kuramitsu
Shomei
S
Ryozawa
Kanako
K
Yoshida
Toshiyuki
T
Tanaka
Sayaka
S
Mori-Iwamoto
Shin-ichiro
S
Maehara
Yoshihiko
Y
Maehara
Isao
I
Sakaida
Kazuyuki
K
Nakamura
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity*; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D015536:Down-Regulation; D055551:HSP27 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011760:Pyrrolidinones / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D001559:Benzhydryl Compounds; D055551:HSP27 Heat-Shock Proteins; C410027:KNK 437; D011760:Pyrrolidinones; D003841:Deoxycytidine; D000093542:Gemcitabine