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

Publication ,  Journal Article
Rangwala, F; Williams, KP; Smith, GR; Thomas, Z; Allensworth, JL; Lyerly, HK; Diehl, AM; Morse, MA; Devi, GR
Published in: BMC Cancer
September 10, 2012

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).

Duke Scholars

Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

September 10, 2012

Volume

12

Start / End Page

402

Location

England

Related Subject Headings

  • Time Factors
  • Thymidylate Synthase
  • Sorafenib
  • Reverse Transcriptase Polymerase Chain Reaction
  • Phenylurea Compounds
  • Oxides
  • Oncology & Carcinogenesis
  • Niacinamide
  • Liver Neoplasms
  • Inhibitory Concentration 50
 

Citation

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Rangwala, F., Williams, K. P., Smith, G. R., Thomas, Z., Allensworth, J. L., Lyerly, H. K., … Devi, G. R. (2012). Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer, 12, 402. https://doi.org/10.1186/1471-2407-12-402
Rangwala, Fatima, Kevin P. Williams, Ginger R. Smith, Zainab Thomas, Jennifer L. Allensworth, H Kim Lyerly, Anna Mae Diehl, Michael A. Morse, and Gayathri R. Devi. “Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.BMC Cancer 12 (September 10, 2012): 402. https://doi.org/10.1186/1471-2407-12-402.
Rangwala F, Williams KP, Smith GR, Thomas Z, Allensworth JL, Lyerly HK, et al. Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer. 2012 Sep 10;12:402.
Rangwala, Fatima, et al. “Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.BMC Cancer, vol. 12, Sept. 2012, p. 402. Pubmed, doi:10.1186/1471-2407-12-402.
Rangwala F, Williams KP, Smith GR, Thomas Z, Allensworth JL, Lyerly HK, Diehl AM, Morse MA, Devi GR. Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer. 2012 Sep 10;12:402.
Journal cover image

Published In

BMC Cancer

DOI

EISSN

1471-2407

Publication Date

September 10, 2012

Volume

12

Start / End Page

402

Location

England

Related Subject Headings

  • Time Factors
  • Thymidylate Synthase
  • Sorafenib
  • Reverse Transcriptase Polymerase Chain Reaction
  • Phenylurea Compounds
  • Oxides
  • Oncology & Carcinogenesis
  • Niacinamide
  • Liver Neoplasms
  • Inhibitory Concentration 50