当前位置： SCI文献检索 > BMC CANCER期刊下所有文献 > Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.

Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.

Abstract：

BACKGROUND:Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5-FU), in both hepatic tumor cells and stromal cells. METHODS:Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. RESULTS:Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC(50): 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC(50): 11.8 μM in LX2; 9.9 μM in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48-72 hr) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. CONCLUSIONS:ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC).

journal_name

BMC Cancer

journal_title

BMC cancer

authors

Rangwala F,Williams KP,Smith GR,Thomas Z,Allensworth JL,Lyerly HK,Diehl AM,Morse MA,Devi GR

doi

10.1186/1471-2407-12-402

subject

Has Abstract

pub_date

2012-09-10 00:00:00

pages

402

issn

1471-2407

pii

1471-2407-12-402

journal_volume

pub_type

杂志文章

在线工具

Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.