One of the hallmarks of advanced prostate cancer is a faulty PTEN tumor suppressor gene. Now, after screening compounds for their effect on cells lacking PTEN, scientists have discovered that a natural insecticide called deguelin can kill such cells by disrupting their energy supply.
Deguelin belongs to a class of drugs known as mitochondrial inhibitors. The drugs block the action of mitochondria.
Mitochondria are the tiny compartments inside cells that convert glucose in the cell into molecules of adenosine triphosphate (ATP), which serve as units of energy for fueling the various workings of the cell.
Scientists at Cold Spring Harbor Laboratory in New York found that treating cells lacking PTEN with some types of mitochondrial inhibitor caused the cells to use glucose from their environment to make ATP and then transport it into their mitochondria to preserve them.
It is as though cells without PTEN, explains study leader Lloyd Trotman, a professor at Cold Spring Harbor Laboratory, are driven to “consume vast quantities of glucose” to help their mitochondria survive. They do this to the point where they run out of fuel and die.
The researchers describe their work — which included the use of a genetic mouse model of metastatic prostate cancer that was developed by Prof. Trotman’s group — in a paper now published in the journal Cell Reports.
They suggest that their findings show that, at the right dose, certain mitochondrial inhibitors such as deguelin — and another that they identified called rotenone — may be able to kill prostate cancer cells without harming healthy cells.
However, they also note that the timing and conditions have to be just right – for example, the drug would not work if glucose levels are high.
“The hope is,” Prof. Trotman explains, “that carefully timed administration of these drugs can generate a much better window of selective killing.”
In the vast majority of cases, prostate cancer is diagnosed before the disease has started to spread. While the cancer is in this localized state, it is much easier to treat, and the 5-year survival rate is close to 100 percent.
However, once the cancer has become metastatic — that is, it has spread and set up new tumors in other parts of the body — it is much harder to treat.
For men diagnosed with metastatic or advanced prostate cancer, the average 5-year survival rate is 29 percent.
In their study paper, the authors note that a “hallmark of advanced prostate cancer” is that two tumor suppressor genes — PTEN and p53 — do not work properly because they are mutated.
Faulty tumor suppressor genes, on the other hand, fail to carry out these functions and give rise to faulty cells that can grow uncontrollably and cause cancer.
Prof. Trotman and colleagues suggest that, of the 3 million men in the U.S. who have prostate cancer, “roughly 100,000 carry cancers with co-mutation of [PTEN and p53].”
This “prompted” them to look for drugs that might work specifically against prostate cancers that carry mutated PTEN and p53.
However, because “several studies” have shown that loss only of p53 does not give rise to prostate cancer, they decided to focus on PTEN.
The researchers began the study by running a series of experiments using cells with and without PTEN.
They found that deguelin had the capacity to kill both types of cell, but the dose required to kill cells with PTEN (the normal cell model) was 500 times higher than the dose required to kill cells without PTEN (the cancer cell model).
They also discovered that the drug had a much stronger effect on the cells without PTEN because their mitochondria were consuming ATP “instead of producing it.”
“That’s the exact opposite,” Prof. Trotman says, “of what mitochondria are supposed to be doing. Mitochondria are supposed to generate ATP for the rest of the cell.”
Finally, when they then tested deguelin in their mouse model of “lethal” metastatic prostate cancer, the researchers found that it stopped the cancer progressing.
The researchers suggest that the “vulnerability” that their findings have identified in PTEN-deficient cells may pave the way for “highly selective targeting of incurable” prostate cancer using mitochondrial inhibitors.
Metformin, the widely prescribed diabetes drug, is also a mitochondrial inhibitor and is already being tested in clinical trials as an anti-cancer treatment.
The authors note that in the case of prostate cancer, treatment with metformin seems to reduce disease deaths but not incidence.
“This suggests,” they add, “that metformin may preferentially target aggressive [prostate cancer],” and there are currently trials trying to find this out. They propose that their new findings “contribute to these efforts.”
However, they note that their study also suggests that one of the conditions necessary for mitochondrial inhibitors to have “maximal selective killing” power is “depletion of tumor cell glucose supplies.”
This would indicate the need for a treatment scenario that is opposite to that of diabetes, in which metformin is taken just after a meal when blood glucose levels are high.
The authors conclude:
“Our results instead suggest that greater selectivity might be achieved if drugs are given when blood glucose levels are low.”