Effect of Combination of Anticancer Agents and Nitroimidazoles on the Survival of Human Hepatocellular Carcinoma Cells under Hypoxic Conditions.
10.4174/jkss.2009.76.6.337
- Author:
Sun Ha LIM
1
;
June Yeob LEE
;
Sung Hwan PARK
;
You Hee KIM
;
Hun Suk SUH
;
Jae Bok PARK
;
Jongwon LEE
Author Information
1. Department of Biochemistry, College of Medicine, Catholic University of Daegu, Korea. leejw@cu.ac.kr
- Publication Type:Original Article
- Keywords:
Anticancer agent;
Nitroimidazole;
Hypoxia;
Combination therapy;
Apoptosis
- MeSH:
Anoxia;
Antineoplastic Agents;
Apoptosis;
Breast Neoplasms;
Carcinoma, Hepatocellular;
Cell Count;
Cell Culture Techniques;
Cell Survival;
Dactinomycin;
Dimetridazole;
DNA Fragmentation;
Doxorubicin;
Epirubicin;
Etanidazole;
Etoposide;
Glucose;
Humans;
Lactic Acid;
Metronidazole;
Misonidazole;
Mitomycin;
Nitroimidazoles;
Ornidazole;
Oxygen;
Tinidazole
- From:Journal of the Korean Surgical Society
2009;76(6):337-347
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
PURPOSE: In a previous study, we have shown that anticancer agents inhibiting topoisomerases improve survival of tumor cells under hypoxic condition. In the present study, we evaluated whether and how cell survival effect of the anticancer agents under hypoxic conditions could be eliminated by the addition of nitroimidazoles, a class of bioreductive agents. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with different combinations of pimonidazole (1~1,000 microg/ml) and doxorubicin (0.1 or 1 microg/ml) concentrations under different O2 concentrations [1, 3, 5, 10 and 21 O2]. Then cell numbers, glucose concentrations and lactic acid concentrations in the medium were measured, and DNA fragmentation assay was performed. Finally, different combinations of nitroimidazoles, such as pimonidazole, misonidazole, etanidazole, tinidazole, metronidazole, ornidazole or dimetridazole, and anticancer agents, such as doxorubicin, campothecin, epirubicin, dactinomycin, etoposide or mitomycin C was added to the cell culture medium under hypoxic conditions (1% O2). RESULTS: Pimonidazole at a concentration of 100 microg/ml eliminated cell survival effect of doxorubicin at the concentrations of 0.1 and 1 microg/ml under hypoxic condition (1% O2) by promoting apoptosis. Almost all the cells died even after 24 hours of incubation for all the oxygen concentrations at a combination of 100 microg/ml pimonidazole and 1 microg/ml doxorubicin. Finally, pimonidazole at a concentration of 100 microg/ml, and misonidazole or etanidazole at a concentration of 1,000 microg/ml eliminated cell survival effect of all the anticancer agents tested under hypoxic condition. CONCLUSION: Combination therapy of doxorubicin (adriamycin) with pimonidazole can maximize dororubicin efficacy by eliminating cell survival effect of doxorubicin under hypoxic conditions in treating solid tumors, such as breast cancer.
