TY  - JOUR
AU  - Liese, Juliane
AU  - Hinrichs, Tobias M
AU  - Lange, Matthias
AU  - Fulda, Simone
TI  - Cotreatment with sorafenib and oleanolic acid induces reactive oxygen species-dependent and mitochondrial-mediated apoptotic cell death in hepatocellular carcinoma cells.
JO  - Anti-cancer drugs
VL  - 30
IS  - 3
SN  - 0959-4973
CY  - [S.l.]
PB  - Ovid
M1  - DKFZ-2020-01925
SP  - 209 - 217
PY  - 2019
AB  - Hepatocellular carcinoma (HCC) is the most common liver malignancy, and the lack of effective chemotherapies underlines the need for novel therapeutic approaches for this disease. Recently, we discovered a novel synergistic induction of cell death by combining sorafenib, the only routinely used palliative chemotherapeutic agent, and the triterpenoid oleanolic acid (OA). However, the underlying mechanisms of action have remained obscure. Here, we report that sorafenib and OA acted in concert to trigger mitochondria-mediated apoptotic cell death, which is dependent on reactive oxygen species (ROS). Sorafenib/OA cotreatment significantly increased ROS production, which was prevented by the ROS scavengers α-tocopherol and MnTBAP. Importantly, rescue experiments showed that ROS were required for sorafenib/OA-induced apoptosis as ROS scavengers protected HCC cells against cell death. In addition, sorafenib and OA cotreatment cooperated to decrease myeloid cell leukaemia-1 expression and to activate Bak, two events that were prevented by ROS scavengers. Bak activation was accompanied by the loss of mitochondrial membrane potential, followed by PARP cleavage, DNA fragmentation and, finally, apoptotic cell death in HCC cells. By providing new insights into the molecular regulation of sorafenib/OA-mediated and ROS-dependent cell death, our study contributes toward the development of novel treatment strategies to overcome sorafenib resistance in HCC.
KW  - Antineoplastic Agents: pharmacology
KW  - Apoptosis
KW  - Carcinoma, Hepatocellular: drug therapy
KW  - Carcinoma, Hepatocellular: metabolism
KW  - Carcinoma, Hepatocellular: pathology
KW  - Cell Proliferation
KW  - Drug Therapy, Combination
KW  - Humans
KW  - Liver Neoplasms: drug therapy
KW  - Liver Neoplasms: metabolism
KW  - Liver Neoplasms: pathology
KW  - Membrane Potential, Mitochondrial: drug effects
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mitochondria: pathology
KW  - Oleanolic Acid: pharmacology
KW  - Reactive Oxygen Species: metabolism
KW  - Sorafenib: pharmacology
KW  - Tumor Cells, Cultured
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - Reactive Oxygen Species (NLM Chemicals)
KW  - Oleanolic Acid (NLM Chemicals)
KW  - Sorafenib (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30640794
DO  - DOI:10.1097/CAD.0000000000000750
UR  - https://inrepo02.dkfz.de/record/163644
ER  -