Laboratory tests have shown that statins, which are drugs used to control cholesterol, can kill ovarian cancer cells. But tests on human patients have yielded mixed results. Could choosing the right statin at the right dose, and excluding dietary sources of a compound that blocks the statin, be effective?
So suggests a new study led by Keele University in the United Kingdom and recently published in the journal Scientific Reports.
Ovarian cancer is cancer that starts in the cells of the ovaries, the almond-sized female organs that produce eggs for reproduction and the hormones estrogen and progesterone. A woman’s body normally contains two ovaries, which are located in the pelvis, with one on each side of the uterus.
The ovaries are made up of three main types of cell: epithelial, germ, and stromal cells. Any of these cells can give rise to cancer, but most ovarian tumors start in the cells that cover the outer surface of the organ, or epithelial cells.
Ovarian cancer is the tenth most common cancer in women in the United States. Although it only accounts for around 3 percent of all cancers in women, it causes more deaths in women than any other reproductive system cancer.
The Centers for Disease Control and Prevention (CDC) estimate that in 2014, 21,161 women in the U.S. found out that they had ovarian cancer and 14,195 died of the disease.
In their study paper, the researchers explain that there is a shortage of effective treatments for ovarian cancer.
Most patients start off by responding well to chemotherapy, but unfortunately, in the majority of cases, the cancer returns and eventually develops resistance to the treatment.
New drugs that target specific molecules are starting to have an effect. These include, for example, PARP inhibitors that stop cancer cells being able to use an enzyme called PARP to repair their DNA.
However, even with these new treatments, the survival rate for ovarian cancer patients is still poor compared with many other cancers. At present, only around 40 percent of patients survive for longer than 5 years.
The researchers say that there is still a need to find new treatments, and one way to do this is to investigate drugs used to treat other diseases.
Statins work by blocking an enzyme called hydroxymethylglutarate coenzyme-A reductase (HMGCR), which helps to make a precursor of low-density lipoprotein, or “bad” cholesterol. They also stop cells producing a compound called geranylgeraniol, which is present in some foods including rice and sunflower oil.
Laboratory studies have already shown that statins can kill ovarian cancer cells. There is also evidence, note the researchers, that the same HMGCR enzyme that statins block to reduce cholesterol also plays various roles in promoting cancer.
However, despite these promising observations, when statins have been tested in human cancer patients, the results have been disappointing.
The researchers – led by Dr. Alan Richardson, a reader in pharmacology in the School of Pharmacy at Keele University – suggest that there could be a number of reasons for the failure of statins to treat cancer. One reason they suggest is that the problem might lie with the size and frequency of dosage to ensure the continual targeting of the HMGCR enzyme.
They also discuss other properties of statins that might be important. For example, they suggest that statins with a longer metabolic half-life are more potent at killing cancer cells, and they also note that differences in their molecular structure might also be important.
Through such arguments, the researchers make a case for investigating a statin called pitavastatin, which has a long metabolic half-life and whose structure suggests that it is a potent inhibitor of the HMGCR enzyme. They also note that there have been no reports of clinical trials of pitavastatin’s effects against cancer.
The team first tested the effect of pitavastatin against cancer cells in the laboratory. They found that the statins triggered cell death in ovarian cancer cells, but also that this could be blocked by the presence of geranylgeraniol.
Further tests on mouse models of ovarian cancer showed that the tumors shrank when the mice were treated with pitavastatin as well as fed a diet lacking in geranylgeraniol.
However, when the mice’s diet was supplemented with geranylgeraniol, the ovarian cancer tumors continued to grow even after treatment with pitavastatin.
“Our research found that the tumor-inhibiting effects of pitavastatin in mice were limited when dietary geranylgeraniol was present.”
Dr. Alan Richardson
“This suggests that patients’ diet must be controlled for statins to be maximally effective in the treatment of cancer,” note the authors. “More generally, clinical trials of drugs which affect metabolic processes may need to take into account patients’ diet.”
Dr. Richardson explains, “Statins work in cancer by preventing cancer cells making geranylgeraniol. However, geranylgeraniol is present in various foods including sunflower oil and some rice, so in future clinical trials, we need to carefully control diet to limit geranylgeraniol.”