This Compound in Foods Found to Limit Effectiveness of Ovarian Cancer Drug

Pitavastatin targets HMGCR in ovarian cancer, and it has shown to be capable of regressing Ovcar-4 tumor xenographs. However, recent studies have shown that if a diet includes geranylgeraniol, the effectiveness of pitavastatin may be limited or stopped.

Treating ovarian cancer

Unfortunately, it is relatively agreed upon that ovarian cancer treatment remains largely inadequate. While it is common for those with ovarian cancer to respond to chemotherapy, it also happens quite often that they will relapse and the disease will then be able to resist the treatment.

Now, molecularly-targeted therapies are more widely available and impactful, like PARP inhibitors, but it still remains that only around 40 percent of these patients will survive longer than 5 years. Clearly, it is necessary to find new therapies. One idea that many are looking further into is to redeploy treatments and drugs that are in use in other diseases.

More about statins

Statins are able to reduce plasma cholesterol by way of inhibiting hydroxymethylgluterate Coenzyme-A reductase (HMGCR). This prevents the synthesis of mevalonate, which comes before cholesterol, and farsenol and geranylgeraniol, which are isoprenoids. They are utilized in order to make alterations to many GTPases, which then become stuck to the membrane. Securing it as such is crucial for the GTPases to properly function. Many of the smaller GTPases are oncogenes, which means that there is also a reason, mechanistically, to interfere with the prenalytion in cancer.

HMCGR is a metabolic oncogene that promotes the growth of tumors and works with Ras in order to change cells that are in colony forming assays. Research has recently shown that it is possible that the expression of HMGCR can be heightened in cancer cells by wild-type or gain-of-function mutants of TP53. This mutation is capable of adding to the amount of p53 protein, due to the reduction of MDM-3 dependent negative feedback loop, which is usually responsible for maintaining p53 protein levels. It is crucial to keep in mind that the mutation of TP53 is almost always present in ovarian cancer.

HMGCR expression is deregulated in a sizable portion of ovarian cancers. This is backed by immonuhistochemical research that has linked HMGCR expression with around 65 percent of ovarian cancers, and sometimes other cancers as well. Now, the inhibition of HMGCR by statin is proposed to change the expression of several genes that lead to carcinogenesis. When combined, these pieces of data propose that inhibition of HMCGR by statins are likely to be of assistance when treating cancer. This is backed by epidemiological research that have discovered a link between statin use to control hypercholesterolemia and a lowered death rate in a few different cancers, including ovarian cancer.

Negative clinical trial results

While there have certainly been positive observations, the clinical trials that have been put forward have not had particularly noteworthy results. There are many reasons why the clinical trials may have shown to be unsuccessful. Many utilized the dose of a statin which is usually put forth to treat hypercholesterolemia, and those doses can cause a plasma concentration of drug which is significantly lower than the concentration that has shown to have an effect on cell death. However, this is not a foolproof explanation, as clinical trials that have utilized closer to the maximum tolerated dose have also proved to be unsuccessful. The researchers were able to depict that what is needed is continual inhibition of HMGCR to kill cells in vitro because 12-hour cycles of simvastatin exposure combined with 12-hour breaks from drugs are able to entirely abrogate the cytotoxic activity of simvastatin in vitro. What this means is that short half-life statins, like simvastatin, simply administered once a day are not likely to be effective in properly inhibiting HMGCR. This is especially true if high doses are not utilized.

Hydrophobic statins may be better due to being more potent inducers of cell death, in comparison to hydrophilic statins. Pitavastatin is particularly important because it is the sole statin able to have both long metabolic half-life that inhibits HMCGR continually with two doses a day and also have a lipophilic structure that causes it to be potent. Clinical trials have not yet been reported, but there remain debates surrounding the effectiveness in cancer treatments.

The study

The researchers analyzed the activity against many other ovarian cancer cell lines in order to prove that clinical trials are worthy. They were able to show that pitavastatin induces apoptosis in the cells of ovarian cancer. But, their findings were not without bumps along the way, although you could definitely say the bumps in themselves were crucial.

They found that when geranylgeraniol interacts with cells, the possibility of dietary isoprenoids stopping the proper function of statins was significantly raised. This was discovered by analyzing Ovcar-4 ovarian cancer xenografts in mice that were given a diet that did not include geranylgeraniol, and the xenografts were seen to regress when given pitavastatin. When they were given a diet including geranylgeraniol, the tumor's growth was unaffected and continues. Therefore, the researchers were able to show that the pitavastatin will only be effective in those who control their diet.

It also showed the need in clinical trials to take patients' diets into consideration, as without this specification it is likely that certain conclusions about the prospective medication or treatment will be made, when in reality the issue may be the patient's diet alone that is interfering with the treatment.

Results

The first results the researchers sought was to confirm HMGCR is often present in ovarian cancer cell lines, which they succeeded in. They showed that the expression of HMGCR was actually more present in each of the 12 cell lines that they looked into than in regular ovarian epithelial cells, which included Ovcar-4, COV-318, COV-362, FuOv1, and Ovsaho cells, which had previously been considered the most authentic cell line models of high-grade serous ovarian cancer.

When attempting to see if dysfunction of TP53 could possible lead to changed HMGCR expression in ovarian cancer cells, the researchers ectopically expressed wild-type and R175H, R248W, and R273H gain-of-function p53 variants in SkOv-3 ovarian cancer cells. Specifically, they had to lack the endogenous p53 protein to be a part of the study. They did not find P53 in SkOv-3 cells that were transfected with the vector, but transfection among each of the three plasmids encoding TP53 and its variants resulted in heightened levels of HMGCR when compared to the cells that were transfected with the vector. Then, expression was inhibited in order to see if pre-existing mutations in TP53 (including its variants) resulted in heightened expression of HMCGR. It was found to significantly decrease levels of p53, HMGCR protein, HMGCR, and mRNA.

Final thoughts

The research progressed to show that pitavastatin capable of inhibiting the growth of cultures of cells that would normally resist carboplatin, which led to further belief that pitavasatin could aid in treating diseases that are drug-resistant. This made a significant impact in the research, as it is certainly a breakthrough, but along the way when it was found that the presence of geranylgeraniol can impact the effectiveness, the study depicted the importance in isolating diet from the treatment, in order to see the efficacy of the drug or treatment itself.

Reference

https://www.nature.com/articles/s41598-017-05595-4