The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action.
This study examined the anti-metastatic effects of oxythiamine (OT) both in cell culture and in vivo. Cell culture results revealed that OT (0-20 microM) significantly inhibited the invasion and migration (IC(50) = 8.75 microM) of Lewis lung carcinoma (LLC) cells. These effects of OT were accompanied by the inhibition of metalloproteinases-2 and -9 (MMP-2, MMP-9), urokinase-type plasminogen activator (uPA) activities and by the increases in protein expression of tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1, TIMP-2). We then implanted (s.c.) C57BL/6 mice with LLC cells and supplemented the mice with a low- or a high-dose of OT (250 or 500 mg/kg BW) daily for 5 wk. During the 5-wk period, OT supplementation decreased plasma MMP-2 activity in a dose-dependent manner, and this effect was significant after 4 wk of tumor cell implantation. Tumor metastasis was found to confine to the lungs of mice injected with the tumor cells. High-OT supplementation strongly lowered the number and area of tumors and inhibited protein expression of MMP-2 and MMP-9 in the lungs. In addition, high-OT supplementation markedly decreased the extent of proliferating cell nuclear antigen (PCNA) staining in the lungs. By contrast, OT supplementation increased TIMP-1 and -2 protein expression in the lungs. These results demonstrate that OT supplementation attenuates tumor cell metastasis, possibly via inhibition of protein expression of MMPs, extent of PCNA staining and via increase of proteins expression of TIMPs.
Yang
Chih-Min
CM
Department of Food Science and Biotechnology, National Chung Hsing University, 250 Kuo Kuang Road, Taichung, 402, Taiwan, ROC.
Liu
Yi-Zih
YZ
Liao
Jiunn-Wang
JW
Hu
Miao-Lin
ML
D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009368:Neoplasm Transplantation; D010119:Oxythiamine / Q000627:therapeutic use*
D010119:Oxythiamine
Ann Surg Oncol. 2002 Aug;9(7):668-74
12167581
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Cancer Res. 1997 Oct 1;57(19):4242-8
9331084
Biol Chem. 1997 Mar-Apr;378(3-4):151-60
9165065
Nihon Rinsho. 1995 Jul;53(7):1805-10
7630023
Cancer Res. 1996 Jan 1;56(1):190-6
8548762
Vet Pathol. 2005 Jul;42(4):405-26
16006601
Oncology. 1976;33(5-6):250-2
1026857
Acta Biochim Pol. 2007;54(2):315-22
17502925
Anticancer Res. 1998 Jan-Feb;18(1B):595-602
9568183
FEBS Lett. 1999 Jul 30;456(1):113-8
10452541
Nature. 1987 Apr 2-8;326(6112):515-7
2882423
Cancer Res. 2003 Jun 1;63(11):2940-7
12782601
Int J Cancer. 2006 Dec 15;119(12):2733-41
17019714
Invasion Metastasis. 1989;9(3):192-208
2722434
Cancer Res. 1998 Mar 1;58(5):1048-51
9500469
Int J Cancer. 1995 Nov 27;63(5):680-7
7591285
FASEB J. 1994 Apr 1;8(6):401-7
7513289
Cancer. 1996 Apr 15;77(8 Suppl):1676-80
8608561
Int J Oncol. 1998 Jun;12(6):1343-8
9592197
Anal Biochem. 1994 May 1;218(2):325-9
8074288
Cancer Res. 2007 Apr 1;67(7):3310-9
17409440
Med Hypotheses. 1998 Jun;50(6):501-6
9710324
FASEB J. 1999 May;13(8):781-92
10224222
Arch Pathol Lab Med. 1987 Sep;111(9):841-5
2888448
Biochim Biophys Acta. 2005 May 25;1755(1):37-69
15907591