Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents.
Cancer cells acquire drug resistance via various mechanisms including enhanced cellular cytoprotective and antioxidant activities. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation and drug resistance. We aimed to investigate roles of HO-1 in human cholangioc...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3325916?pdf=render |
| _version_ | 1811279256867569664 |
|---|---|
| author | Sarinya Kongpetch Veerapol Kukongviriyapan Auemduan Prawan Laddawan Senggunprai Upa Kukongviriyapan Benjaporn Buranrat |
| author_facet | Sarinya Kongpetch Veerapol Kukongviriyapan Auemduan Prawan Laddawan Senggunprai Upa Kukongviriyapan Benjaporn Buranrat |
| author_sort | Sarinya Kongpetch |
| collection | DOAJ |
| description | Cancer cells acquire drug resistance via various mechanisms including enhanced cellular cytoprotective and antioxidant activities. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation and drug resistance. We aimed to investigate roles of HO-1 in human cholangiocarcinoma (CCA) cells for cytoprotection against chemotherapeutic agents. KKU-100 and KKU-M214 CCA cell lines with high and low HO-1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents, gemcitabine (Gem) and doxorubicin. Inhibition of HO-1 by zinc protoporphyrin IX (ZnPP) sensitized both cell types to the cytotoxicity of chemotherapeutic agents. HO-1 gene silencing by siRNA validated the cytoprotective effect of HO-1 on CCA cells against Gem. Induction of HO-1 protein expression by stannous chloride enhanced the cytoprotection and suppression of apoptosis caused by anticancer agents. The sensitizing effect of ZnPP was associated with increased ROS formation and loss of mitochondrial transmembrane potential, while Gem alone did not show any effects. A ROS scavenger, Tempol, abolished the sensitizing effect of ZnPP on Gem. Combination of ZnPP and Gem enhanced the release of cytochrome c and increased p21 levels. The results show that HO-1 played a critical role in cytoprotection in CCA cells against chemotherapeutic agents. Targeted inhibition of HO-1 may be a strategy to overcome drug resistance in chemotherapy of bile duct cancer. |
| first_indexed | 2024-04-13T00:51:26Z |
| format | Article |
| id | doaj.art-c74759e611fd4083beed622fbe714e4a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T00:51:26Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c74759e611fd4083beed622fbe714e4a2022-12-22T03:09:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3499410.1371/journal.pone.0034994Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents.Sarinya KongpetchVeerapol KukongviriyapanAuemduan PrawanLaddawan SenggunpraiUpa KukongviriyapanBenjaporn BuranratCancer cells acquire drug resistance via various mechanisms including enhanced cellular cytoprotective and antioxidant activities. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation and drug resistance. We aimed to investigate roles of HO-1 in human cholangiocarcinoma (CCA) cells for cytoprotection against chemotherapeutic agents. KKU-100 and KKU-M214 CCA cell lines with high and low HO-1 expression levels, respectively, were used to evaluate the sensitivity to chemotherapeutic agents, gemcitabine (Gem) and doxorubicin. Inhibition of HO-1 by zinc protoporphyrin IX (ZnPP) sensitized both cell types to the cytotoxicity of chemotherapeutic agents. HO-1 gene silencing by siRNA validated the cytoprotective effect of HO-1 on CCA cells against Gem. Induction of HO-1 protein expression by stannous chloride enhanced the cytoprotection and suppression of apoptosis caused by anticancer agents. The sensitizing effect of ZnPP was associated with increased ROS formation and loss of mitochondrial transmembrane potential, while Gem alone did not show any effects. A ROS scavenger, Tempol, abolished the sensitizing effect of ZnPP on Gem. Combination of ZnPP and Gem enhanced the release of cytochrome c and increased p21 levels. The results show that HO-1 played a critical role in cytoprotection in CCA cells against chemotherapeutic agents. Targeted inhibition of HO-1 may be a strategy to overcome drug resistance in chemotherapy of bile duct cancer.http://europepmc.org/articles/PMC3325916?pdf=render |
| spellingShingle | Sarinya Kongpetch Veerapol Kukongviriyapan Auemduan Prawan Laddawan Senggunprai Upa Kukongviriyapan Benjaporn Buranrat Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. PLoS ONE |
| title | Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. |
| title_full | Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. |
| title_fullStr | Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. |
| title_full_unstemmed | Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. |
| title_short | Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. |
| title_sort | crucial role of heme oxygenase 1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents |
| url | http://europepmc.org/articles/PMC3325916?pdf=render |
| work_keys_str_mv | AT sarinyakongpetch crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents AT veerapolkukongviriyapan crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents AT auemduanprawan crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents AT laddawansenggunprai crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents AT upakukongviriyapan crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents AT benjapornburanrat crucialroleofhemeoxygenase1onthesensitivityofcholangiocarcinomacellstochemotherapeuticagents |