Abstract
Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 µM doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.
Highlights
Intermediate hepatocellular carcinoma (HCC) is treated with image-guided transcatheter tumor therapy by locally infusing a chemotherapeutic agent in a drug delivery system, so called transarterial chemoembolization (TACE) [1,2,3,4]
Cell viability of HepG2 cells grown under hypoxic conditions declined to 81% from 6 to 72 h compared to normoxic conditions (Table 1)
We present our findings that three established and commonly used liver cancer cell lines (HepG2, Huh7, and SNU449 ) have critically different responses to chemotherapy and hypoxia
Summary
Intermediate hepatocellular carcinoma (HCC) is treated with image-guided transcatheter tumor therapy by locally infusing a chemotherapeutic agent in a drug delivery system, so called transarterial chemoembolization (TACE) [1,2,3,4]. This treatment has two purposes: to deliver the drug close to the tumor site and to cause an arterial embolization close to the cancer region [5]. By infusing the drug close to the tumor (locoregional), the tumor is exposed to a high concentration of the drug, which will lead to an increased antitumor effect, while reducing systemic exposure and side-effects [6]. DOX has been used for the treatment of advanced HCC for over 30 years, but definitive evidence that DOX as a systemic treatment improves survival has not been provided [11], while the survival benefit in combination with chemoembolization has been generally accepted [12]
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