A new drug recently approved in the US as a first-line treatment for relapsing forms of multiple sclorosis, appears also to kill ovarian cancer cells in a way that overcomes drug resistance, a major obstacle to curing ovarian cancer; the breakthrough discovery still has to be confirmed by trials, but because the drug, code-named FTY720 (also known as fingolimod), is already approved for other reasons, the Australian and Chinese research team said it should not take as long to get to market as a brand new one.
The findings of the study, led by Pu Xia, professor and head of the Signal Transduction Program at the Centenary Institute in Sydney Medical School at the University of Sydney, are published in the 16 November issue of the journal Autophagy.
Other studies have already found that FTY720 fights tumors in other cancers, but this is the first time it has been studied in ovarian cancer.
Xia and colleagues said their discovery is a breakthrough because they found FTY720 kills ovarian cancer cells in a different way to that of current anti-cancer drugs.
They said in a statement that the new drug had a potent effect in human ovarian cancer cells, even those resistant to the most commonly used chemotherapy drug, cisplatin.
Cisplatin, and other current drugs, kill ovarian cancer cells by triggering apoptosis or programmed cell death, but cancer cells can become resistant by reversing or destroying the process.
But in their research, Xia and colleagues found that FTY720 acts on ovarian cancer cells via a different route: it uses a process called necrosis which is irreversible but still deadly, and they said once the cancer cells travel down this path to destruction, they cannot resist, repair and relapse.
“In contrast to the previously reported cytotoxicity of FTY720 in many other cancer cell types, FTY720 kills ovarian cancer cells independent of caspase 3 activity and induces cellular swelling and cytoplasmic vacuolization with evident features of necrotic cell death,” they wrote.
Ovarian cancer is the number one killer of women with gynaecological malignancies over the world; in Australia about 800 women die of it every year.
Xia told the press that one of the reasons ovarian cancer is difficult to treat is because the cancer cells set up a protective shield that resists the chemotherapy drugs. The shield is a natural response to the treatment, and helps the cancer cells survive it.
Xia and colleagues found that the shield uses a process called “autophagy” where cells consume their own non-vital components to help them survive stressful circumstances like starvation and attack by agents like chemotherapy.
But what was quite remarkable about the discovery that FTY720 uses a different path was the parallel finding that even though the ovarian cancer cells still put up the protective shield when under attack by FTY720, the potency of the drug via the necrosis route is strong enough to kill them.
They described the drug as showing a “potent, dose- and time-dependent cytotoxic effect in human ovarian cancer cells”.
They also suggested that if there was a way to switch off the autophagy effect, this could make FTY720 even more effective: “targeting autophagy could augment the anticancer potency”, they wrote.
Although the researchers are thrilled by their discovery, which represents a major first step toward developing a more effective treatment for ovarian cancer, they cautioned that their findings now need to undergo confirmation and scrutiny through pre-clinical and full clinical trials before using FTY720 on women with ovarian cancer.
But because the US Food and Drug Administration (FDA) has already approved an oral dose of the drug (in September this year) for the treatment of multiple sclerosis, and it is also undergoing several clinical trials as an immune suppressor for preventing organ transplant rejection and treating various immune diseases, the researchers are hopeful that it will be available for the treatment of ovarian cancer within the next several years.
“FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: A protective role of autophagy.”
Ning Zhang, Yanfei Qi, Carol Wadham, Lijun Wang, Alessandra Warren, Wen Di and Pu Xia.
Autophagy, Volume 6, Issue 8, Pages 1157 – 1167, 16 November 2010
Additional sources: Centenary Institute, MS Trust.
Written by: Catharine Paddock, PhD