Hepatocellular toxicity of oxalicumone A via oxidative stress injury and mitochondrial dysfunction in healthy human liver cells.

Abstract

The marine‑derived oxalicumone A (POA) has been demonstrated as a potent anti‑tumor bioactive agent for a variety of human carcinoma, but to the best of our knowledge, remains to be evaluated in healthy liver cells. As many drugs distribute preferentially in the liver, the present study aimed to investigate the effects of POA on apoptosis, oxidative stress and mitochondrial function in L‑02 healthy liver cells. A Cell‑Counting kit‑8 assay demonstrated that POA inhibits the proliferation of L‑02 cells in a dose‑ and time‑dependent manner. Furthermore, POA induced apoptosis by increasing the percentage of cells in early apoptosis and the sub‑G1 cell cycle, along with causing S‑phase arrest in L‑02 cells. Additionally, POA activated caspase 3, increased the protein expression levels of Fas ligand and B‑cell lymphoma X‑associated protein, and decreased the expression of the anti‑apoptotic protein B‑cell lymphoma 2. POA additionally reduced the content of GSH and the activity of superoxide dismutase, elevated malondialdehyde and nitric oxide levels, increased reactive oxygen species production and the levels of alanine aminotransferase and aspartate aminotransferase, which suggested that POA induced lipid peroxidation injury in L‑02 cells and that oxidative stress serves an important role. Furthermore, POA caused alternations of mitochondrial function, including an abrupt depletion of adenosine triphosphate synthesis, mitochondrial permeability transition pore opening and depletion of mitochondrial membrane potential in L‑02 cells. These data suggested that POA exerts cytotoxicity, at least in part, by inducing oxidative stress, mitochondrial dysfunction, and eventually apoptosis. Changes in mitochondrial function and oxidative stress by POA may therefore be critical in POA‑induced toxicity in L‑02 cells.

• Authors: Si Shi, Limei Yao, Kunbin Guo, Xiangyu Wang, Qi Wang, Weirong Li
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 17 Issue 1 Pg. 743-752 (Jan 2018) ISSN: 1791-3004 [Electronic] Greece
• PMID: 29115483 (Publication Type: Journal Article)

Chemical References

• Chromones
• Reactive Oxygen Species
• oxalicumone A
• Malondialdehyde

Topics

• Apoptosis (drug effects)
• Cell Line
• Chromones (toxicity)
• Hepatocytes (drug effects, pathology)
• Humans
• Lipid Peroxidation (drug effects)
• Liver (drug effects, injuries, pathology)
• Malondialdehyde (metabolism)
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, pathology)
• Oxidative Stress (drug effects, genetics)
• Reactive Oxygen Species (metabolism)