Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin

Abstract

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.

Functional impairment triggered by altertoxin II (ATXII) in intestinal cells in vitro: cross-talk between cytotoxicity and mechanotransduction

“…In this light, it is prone not only to the activation of the Nrf2/ARE pathway (Jarolim et al 2017), but also to direct reaction with diverse cell structures (Fleck et al 2012; Jarolim et al 2016). To verify if the effect of the toxin on membrane fluidity was related to oxidation/reaction processes involving the epoxide moiety of the molecule, experiments were performed in the presence of the antioxidant NAC (Oommen et al 2016; Raza et al 2016). NAC significantly reverted the effect of the toxin restoring the membrane fluidity to control levels, as well as restoring cell morphological alteration induced by ATXII (Fig.…”

The gold complex auranofin: new perspectives for cancer therapy

“…The toxicity of ROS in these cells was demonstrated by the fact that NAC also prevented auranofin-induced lethality [ 62 ]. Of interest, the DNA damage caused by auranofin-induced ROS seems to be favored by increased membrane fluidity as shown in ovarian cancer cells with higher membrane fluidity (IGROV-1) being more sensitive to auranofin than ovarian cancer cells with lower membrane fluidity (OVCAR-5) [ 63 ]. Altogether, these evidences emphasize that ROS regulation plays a primary role in cancer cell survival and proliferation, and further supports the possible repurposing of auranofin against various cancers due to the pro-oxidative mechanism it triggers.…”

Lipidomic landscape in cancer: Actionable insights for membrane‐based therapy and diagnoses

“…Soraphen A has been shown to increase chemosensitivity by modulating membrane fluidity and enhancing drug uptake 46 . Targeting membrane fluidity also enhanced the sensitivity of ovarian cancer cell lines to auranofin, inducing DNA damage and cellular oxidation 101 . Auranofin has successfully entered Phase 2 clinical trials for the treatment of recurrent epithelial ovarian cancer.…”