Arsenic trioxide inhibits metastatic potential of mouse hepatoma H22 cells in vitro and in vivo.
BACKGROUND
It has been pointed out that only low-dose arsenic trioxide (ATO) presents therapeutic benefits outweighing the toxic side effects. Low-dose ATO can effectively alleviate acute promyelocytic leukemia (APL). However, it is quite challenging in treating solid tumors. The purpose of this study was to investigate the effect of ATO at low concentrations on the metastatic potential of mouse hepatoma H(22) cells and the anti-metastatic mechanism of ATO.


METHODS
The metastatic potential of H(22) cells was evaluated by adhesion, migration and invasion assays after exposure to a low dose of ATO in vitro. The mouse lung metastatic model induced by injection of H(22) cells via the tail vein was adopted for the evaluation of metastatic potential. Different proteins in the lysate of H(22) cells exposed to ATO at different concentrations were investigated by surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Finally, Western blotting analyses were made to detect the expression pattern of MMP-2 and nm23-M1 proteins.


RESULTS
Significant cell death started at ATO concentrations above 2 micromol/L. The growth and adhesion potential of H(22) cells was inhibited in a time- and dose-dependent manner, and the migration and invasion potential of H(22) cells was inhibited in a dose-dependent manner while ATO concentration was below 2 micromol/L. Mice injected with ATO at a dose of 0.5 mg/kg had fewer lung metastases. However, mice injected with ATO at a dose of 2 mg/kg or 4 mg/kg had a high mortality rate and more liver injuries. A total of 15 different protein peaks were identified between the lysate of H(22) cells treated with ATO and controls. Two proteins that peaked at m/z 5302 and 17207 coincided with MMP-2 (fragment) and nm23-M1, respectively. Western blotting analyses demonstrated that MMP-2 and MMP-2 fragments were down-regulated and nm23-M1 was up-regulated in H(22) cells treated with 2 micromol/L ATO for 48 hours.


CONCLUSIONS
ATO at a low dose inhibits the metastatic potential of mouse hepatoma H(22) cells in vitro and in vivo, and involves down-regulation of MMP-2 and up-regulation of nm23-M1.
Zhao
Xian-Shu
XS
Department of Gastroenterology, Fourth Affiliated Hospital, Harbin Medical University, Harbin 150010, China.
Song
Peng-Long
PL
Sun
Bei
B
Jiang
Hong-Chi
HC
Liu
Tie-Fu
TF
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D010087:Oxides / Q000009:adverse effects / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000970:Antineoplastic Agents; D001152:Arsenicals; D054778:NM23 Nucleoside Diphosphate Kinases; D010087:Oxides; C517939:Nme1 protein, mouse; D020778:Matrix Metalloproteinase 2; D000077237:Arsenic Trioxide