Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin.
Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from DNA repair capability of cancer cells, membrane fluidity is also implicated in modulating resistance to chemotherapeutics. We report here that membrane fluidity influences the sensitivity of ovarian cancer cell lines, OVCAR5 and IGROV1, to auranofin. Electron spin resonance (ESR) analysis revealed a more fluidized membrane in IGROV1 compared to OVCAR5. Interestingly, IGROV1 cells were more sensitive to auranofin induced cytotoxicity than OVCAR5. In comparison to OVCAR5, IGROV1 cells also exhibited an increased number of DNA double strand breaks (DSBs) upon auranofin treatment as assessed by 53BP1 immunostaining. Furthermore, correlation analysis demonstrated a strong positive correlation (r=0.856) between membrane fluidity and auranofin sensitivity in these cell lines. Auranofin-treated IGROV1 cells also exhibited increased cellular oxidation and apoptosis. Anti-oxidant, N-acetyl cysteine (NAC) inhibited the cellular oxidation and apoptosis in auranofin-treated ovarian cancer cells suggesting reactive oxygen species (ROS) mediate the anti-cancer properties of auranofin. Overall, our study suggests that auranofin mediates its cytotoxicity via ROS production in ovarian cancer cells which correlates positively with membrane fluidity.
School of Biological Sciences, Plymouth University, Plymouth, PL4 8AA, UK.
Deepu
D
Oommen
School of Biological Sciences, Plymouth University, Plymouth, PL4 8AA, UK.
Nicholas J F
NJ
Dodd
Plymouth Oncology Centre, Derriford Hospital, Plymouth, PL6 8DH, UK.
Dennis
D
Yiannakis
School of Computing, Electronics and Mathematics, Plymouth University, Plymouth, PL4 8AA, UK.
Rana
R
Moyeed
School of Biological Sciences, Plymouth University, Plymouth, PL4 8AA, UK. Electronic address: a.jha@plymouth.ac.uk.
Awadhesh N
AN
Jha
D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects*; D009152:Mutagenicity Tests / Q000379:methods*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018501:Antirheumatic Agents; D017382:Reactive Oxygen Species; D001310:Auranofin
Auranofin; Cell survival; DNA damage; Drug sensitivity; Membrane fluidity; Ovarian cancer