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Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines
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 lin...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517386/ https://www.ncbi.nlm.nih.gov/pubmed/22963400 http://dx.doi.org/10.1186/1471-2407-12-402 |
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author | Rangwala, Fatima Williams, Kevin P Smith, Ginger R Thomas, Zainab Allensworth, Jennifer L Lyerly, H Kim Diehl, Anna Mae Morse, Michael A Devi, Gayathri R |
author_facet | Rangwala, Fatima Williams, Kevin P Smith, Ginger R Thomas, Zainab Allensworth, Jennifer L Lyerly, H Kim Diehl, Anna Mae Morse, Michael A Devi, Gayathri R |
author_sort | Rangwala, Fatima |
collection | PubMed |
description | 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). |
format | Online Article Text |
id | pubmed-3517386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35173862012-12-08 Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines Rangwala, Fatima Williams, Kevin P Smith, Ginger R Thomas, Zainab Allensworth, Jennifer L Lyerly, H Kim Diehl, Anna Mae Morse, Michael A Devi, Gayathri R BMC Cancer Research Article 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). BioMed Central 2012-09-10 /pmc/articles/PMC3517386/ /pubmed/22963400 http://dx.doi.org/10.1186/1471-2407-12-402 Text en Copyright ©2012 Rangwala et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Rangwala, Fatima Williams, Kevin P Smith, Ginger R Thomas, Zainab Allensworth, Jennifer L Lyerly, H Kim Diehl, Anna Mae Morse, Michael A Devi, Gayathri R Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title | Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title_full | Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title_fullStr | Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title_full_unstemmed | Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title_short | Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
title_sort | differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517386/ https://www.ncbi.nlm.nih.gov/pubmed/22963400 http://dx.doi.org/10.1186/1471-2407-12-402 |
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