Possible Involvement of Endoplasmic Reticulum Stress in Hepatotoxicity of Doxorubicin

This is the authors' abstract. We don't add key points for this paper.

Hepatic injury caused by doxorubicin (DOX), an anthracycline antitumor agent, is an important dose-limiting adverse event that may restrict treatment dosage and continuation. This study, using HepG2 cells, examines the involvement of endoplasmic reticulum (ER) stress in DOX-induced hepatic damage. The expression level of targets was measured by real- time polymerase chain reaction (PCR) and Western blot analysis. Cytotoxicity was evaluated by the MTT assay. The gene expression of glucose regulated protein 78 (GRP78) was increased in a time-dependent manner after exposure to DOX, and the expression of X-box binding protein 1 (XBP1) and C/EBP homologous protein (CHOP) was increased correspondingly. Concurrently, increased phosphorylation of eIF2α and c-Jun N-terminal kinase (JNK) was observed. Furthermore, the cytotoxic effect of DOX was significantly suppressed by concurrent exposure to 4-phenylbutyric acid(4-PBA), an ER stress inhibitor. This study suggests that DOX induces ER stress and a proapoptotic response, thereby increasing cytotoxicity in Hepatoblastoma G-derived 2 (HepG2) cells, and may contribute to strategies for reducing anthracycline-induced hepatic injury.