Cell membrane fluidity may determine ovarian cancer response to the anti-rheumatic drug Ridaura (auranofin) currently in trials for epithelial ovarian cancer, researchers found.
The study, “Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin,” published in Mutation Research/Genetic Toxicity and Environmental Mutagenesis, shows that greater rigidity in the cell membrane prevents the cells from absorbing the drug and reduces its ability to kill the cancer.
The anti-rheumatic drug Ridaura is currently under clinical trials in epithelial ovarian cancer (NCT01747798), which accounts for nearly 90 percent of all ovarian cancer cases. Ridaura works by inducing lethal DNA damage in BRCA1 mutated ovarian cancer cells.
Cell membranes consist of lipid bilayers that surround the cells and control the substances that move into the inside or outside of the cells. Studies have reported that cells can increase the rigidity of their membranes (enriching them in cholesterol and sphingomyelin molecules) and impair intracellular drug uptake.
To clarify how plasma membrane fluidity affects the responses of ovarian cancer to Ridaura, the research team led by Drs. Deepu Oommen and Nicholas Dodd, from the Genetic Toxicology & Ecotoxicology Research Group at Plymouth University, used two ovarian cancer cell lines — IGROV1 and OVCAR5.
They used cutting edge technology to determine cell membrane fluidity, as well as cell death and DNA damage in response to Ridaura.
Results showed that IGROV1 cells had a more fluid membrane than OVCAR5, which rendered them more susceptible to Ridaura. Upon Ridaura treatments, the cells exhibited increased cell death and more DNA double strand breaks than OVCAR5 cells.
Awadhesh Jha, professor of toxicology and associate head researcher in the School of Biological Sciences, said in a press release: “Most traditional chemotherapeutic drugs act by damaging the DNA of cells, which leads to cell death. But in order to try and build resistance to this cancer cells evolve by changing their genetic properties and cell membrane rigidity could be one of the confounding factors through which they become resistant to treatment.”
The determination is in line with previous findings showing that chemo-resistant cancer cells often exhibit greater rigidity in their cell membranes. The findings further show that cells with increased membrane fluidity can easily uptake anti-cancer drugs, suggesting that targeting membrane fluidity may be a means to increase the effectiveness of certain drugs.
“If a means to influence membrane fluidity could be achieved, it could enhance a drug’s capability to cause DNA damage within cancer cells and significantly influence treatment outcomes,” Jha said.