Repurposed Drug Clioquinol and Zinc Offer Hope for Advanced Prostate Cancer

The prostate, that walnut-sized gland that resides just below a man's urinary bladder, doesn't typically get much thought until it goes sideways. Sideways for a prostate most frequently happens in middle-aged men and manifests as an enlarged gland. Prostate enlargement is most often the result of a condition termed benign prostatic hyperplasia, aka BPH, and roughly 50% of men in the 50-60 age group have it. When the prostate gland enlarges, it can cause symptoms leading to the prostate "red flag" symptoms.

These red flag symptoms include waking to urinatea 3-4+ times per night, trouble starting the stream, or trouble finishing a pee without dribbling down the leg. If you have any of these symptoms, do yourself a favor and get checked out.

In some men the prostate gland really goes awry and becomes cancerous. About 270,000 men are diagnosed with prostate cancer every year in the US. A guy can hedge his bets by practicing a little preventative medicine such as participating in regular exercise, maintaining a healthy weight, eating cruciferous vegetables and consuming foods and nutrients proven to be preventative.

Over the past 5-10 years some very interesting research has uncovered how a once-normal prostate cells transforms into a prostate cancer cell. This transformation doesn't just magically happen, there are some now well-defined cellular changes that occur. Some of these cell changes may present unique treatment options for men with prostate cancer, and may be especially important for those with advanced disease.

Before jumping right into cellular physiology, a little background on the function of prostate gland is in order. The prostate gland's job is not to be pain in the ass, but rather to alkalinize the sperm should they be lucky enough to be deposited into a vagina.

Vaginas are acidic, and without the alkaline prostatic fluid providing some pH relief, those lucky sperm would likely not live long enough to reach their target. That alkalinizing fluid produced by prostate cells is made possible by the large amount of a compound called citrate. Citrate is a small molecule of big importance. Citrate is one of the compounds used in the Krebs Cycle, aka the citric acid cycle, or the tricarboxylic acid cycle, which is one of the main ways that we humans make energy.

The Krebs cycle is the process cells use to turn food into energy. It takes molecules from carbs, fats, and proteins and breaks them down to make ATP, the fuel cells need to work.

This is important because all human cells require a constant energy source, and certain things in our bodies must always have the energy to carry out their functions- think the heart and brain. If those things run out of energy there's big trouble.

So it turns out that healthy prostate cells accumulate citrate by putting the brakes on the Krebs cycle. These cells slow the metabolic activity of the Krebs cycle and limit energy production by using the mineral zinc. Prostate glands and the cells that make them up contain more zinc than any other part of the body. They are zinc-rich, you might say. This high level of zinc is crucial to the prostate cells' ability to accumulate citrate for those lucky sperm.

The high levels of zinc in prostate cells influence the activity of an enzyme known as m-aconitase. M-aconitase controls the conversion of citrate into isocitrate, a crucial step in the Krebs cycle. High levels of zinc inside the cells inhibits aconitase activity, increasing intracellular citrate levels and inhibiting the Krebs Cycle. On the other hand, low levels of zinc facilitate speeding up m-aconitase activit that decreases citrate levels, and thus speeds up Krebs cycle energy production.

Cancer is a disease of uncontrolled cell division. Initially, a single cell becomes mutated and ends of being reprogrammed. Instead of a healthy cell's programming which tells the cell "reproduce only when needed," cancer cells' faulty programming instructs them to "continually reproduce at all times and at all costs." All this cell replication requires a lot of energy, and the metabolic brakes put on prostate cell energy production by high zinc levels creates an energy problem for would-be prostate cancer cells- with Krebs inhibited, the available energy is restricted.

It has now been repeatedly shown in research that in order for a healthy prostate cell to turn into a prostate cancer cell (PCa) that zinc levels need to be drastically reduced inside the cell. By removing all the zinc, the cell is essentially taking turning on the Kreb's cycle and increasing energy production in cancer cells. Lower intracellular levels of zinc have been found in both early and late-stage prostate cancer cells.

Prostate cancer cells can lower zinc levels by down-regulating ZIP transporters. These transporters normally move zinc through the cell membrane from outside the cell to the inside of the cell and vice versa. Down-regulation of ZIP-1 transporters can drastically reduces intracellular zinc levels.

The concept of the role of zinc and altered citrate matabolism in the development of prostate malignancy. Borrowed from: The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots.

Research has identified a potential treatment for increasing prostate cancer intracellular zinc levels that is independent of ZIP transporters. One of the more interesting is a medication called clioquinol. Clioquinol is a drug that has been historically been used as an antimicrobial. Recently clioquinol been studied as a zinc ionophore, ie a substance which can move zinc across cell membranes. Studies have shown that by using clioquinol to increase intracellular zinc levels, prostate cancer growth rates were decreased by as much as 85% in animal models.

Oral clioquinol was removed from the market in the 1970's after being suspected of causing a specific type of optic neuropathy that was almost exclusively limited to Japan. Recent research suspects that the reason the adverse effects were limited Japanese people was due to genetic variations in that population.

Topical clioquinol use has not been associated with adverse effects and is generally considered safe.

Additionally, several very interesting papers have been published about using clioquinol for prostate cancer. Some have found that in addition to being a zinc ionophore, clioquinol has additional anti-prostate cancer actions:

• Clioquinol was found to suppress androgen receptors in human prostate cancer xenograft models.

• Radio-sensitization of diverse cancer cell lines.

In fact, clioquinol has shown intriguing results with several cancer types including triple negative breast cancer, neuroblastoma, and even myeloma and leukemia.

Hopefully, the research on clioquinol will continue to expand and this research will be translated into successful protocols. Current treatment options for advanced metastatic prostate cancer are limited and a efficacious, non-toxic and inexpensive treatment option is drastically needed.

It is important to remember that cancer is a diverse disease and rarely do two people have identical disease, even if diagnosed with the same type of cancer. Cancer cells can change themselves quickly in response to treatments, supplements, and dietary changes. Treatments should be tailored to the individual and incorporate modern laboratory and diagnostic testing as well as multifaceted treatment protocols. Use the information above to facilitate conversation with your doctors. For successful cancer treatment patients are encouraged to seek out healthcare providers experienced with creating personalized integrative therapies.