Israeli scientists have found that Prozac (fluoxetine), the well-known antidepressant, acts as a highly-effective chemosensitizer, that works at doses well-below its human safety limits.Two new research projects have been published which demonstrate complementary ways in which Israeli scientists are helping to fight the global battle against cancer. In one study, researchers at Tel Aviv University have shown that the well-known antidepressant Prozac can safely boost the effectiveness of chemotherapy against tumors in mice. In the other report, an Israeli researcher, together with American scientists, has discovered that Alopurinol, a drug for treating gout, can reduce the risk of developing cancer of the colon and rectum, the second most common malignancy in the United States.

Despite advances in cancer therapy and in early detection, the battle against cancer is still lost for too many patients. A major factor responsible is the resistance most cancers have (over 80% of patients) towards a broad repertoire of anticancer drugs. Some tumors are known to be resistant to such drugs. In these cases the drugs fail to influence the tumors and they do not shrink.

“One of the projects that we focus on in my lab is the problem of resistance of cells to drugs,” said Professor Rimona Margalit, from the Department of Biochemistry, in Tel Aviv University’s Life Sciences Faculty “It’s really a problem of membrane transport processes which we’re interested in. What we’re trying to do is find something that will stop the pumping of the therapeutic drug out of the tumor cells, so enough of the drug can accumulate in order to kill the cancer cells,” she told ISRAEL21c.

In the highly-acute situation, called multidrug resistance (MDR), nothing happens to the anticancer drug itself. Rather, it is a matter of insufficient supply. In drug-sensitive and in drug-resistant cases, the anticancer drugs permeate the cell. The difference is that in drug-sensitive cases the drugs stay inside the cell, reaching amounts sufficient for cell kill, whereas in drug-resistant cases the drugs do not stay inside the cell. This is due to inherent and acquired pumps, situated in the membrane of the MDR cell, that pump drugs out of the cell at rates much faster than drug permeation.

Consequently, there is too little drug inside the cancer cell – not enough to kill it. Because these pumps are not choosy when it comes to the drugs they pump out, MDR is a problem not only for the current anticancer drugs, but is a high risk for many of the new and future anticancer drugs.

An obvious and seemingly-simple way to overcome MDR is to stop the pumping, allowing sufficient drug accumulation inside the cancer cell, just as in the drug-sensitive cases. This process was named chemosensitization, and agents capable of the act – chemosensitizers.

In reality, this seemingly-simple way turned out to be far from simple — not for lack of pump-stopping agents, but for lack of agents that could be given safely to patients.

Chemosensitizers were found among drugs approved for other non-cancerous indications, but at doses that were way above their safe and approved levels, leading to adverse effects and toxicity, as well exceeding solubility limits.

According to Margalit, substances that seem to work at the beginning are only effective in high doses later on. In such high dosages, the patient suffers from severe side effects.
Ultimately, after three decades of understanding the origins of MDR and three generations of chemosensitizers, MDR is still a major unresolved problem for cancer patients – which makes the TAU discovery all the more significant.

Margalit and her Ph.D. graduate student Dan Peer found that Prozac (fluoxetine), the well-known antidepressant, acts as a highly-effective chemosensitizer, that works at doses well-below its human safety limits, free of the severe dose-related toxicity, adverse-effects and poor solubility that were obstacles to previous chemosensitizers, in the battle against drug-resistance tumors.

The findings, reported in the October 15th issue of Cancer Research, show that Prozac improved the distribution of the chemotherapy medication in cancerous cells in mice. The mice were given Prozac in their drinking water, which reversed MDR in human breast cancer grafts and metastatic lung tumors.

“We arrived at Prozac by chance during a series of controlled studies in the area of drug delivery – which is another project we work on in my lab. We saw a clue to something which we decided to follow up on,” said Margalit.

However, Margalit stressed that the use of Prozac to overcome MDR still requires clinical testing, not only to verify the results but to develop a precise treatment regimen and carefully map out the dosing range.

“We haven’t done any clinical studies on humans. We’re continuing to work toward this end as energetically as we can, but we still need to complete additional animal studies until we can talk to the FDA about human trials. We simply don’t know yet what the combination of Prozac and chemotherapy will do to the patient. An incorrect dosage can do more harm than good, so everybody must be patient, and we need to do everything by the book, which is good — the FDA is one of our best watchdogs,” said Margalit.

Margalit said that if their findings are confirmed in human patients, there will be a “realistic chance” for significant gains in the battle against cancer by making already-approved drugs more effective.

In another equally important breakthrough, Israeli and American researchers have discovered that if taken for at least five years, a simple drug for treating gout can reduce the risk of getting colorectal cancer by 66 percent. Colon cancer is the second-placed killer among American men, and third-placed among American women, according to the American Cancer Society.

At the annual meeting of the American Association for Cancer Research in Seattle last week, Dr. Gad Rennert and Dr. Steve Gruber reported that the drug, Alopurinol, has proven to be a boon for lowering the risk of cancer of the colon and rectum. Before being used clinically, however, the researchers said the drug, conventionally given for a condition that causes inflamed toes, requires additional clinical studies to corroborate their findings.

Rennert (an ICA advisor and head of Clalit Health Services’ National Cancer Registry) and Gruber (of the University of Michigan) based their discovery on a six-year study of 1,781 gout sufferers from Haifa and the North who were treated with Alopurinol for their rheumatic condition and a control group who were not.

It’s not clear how allopurinol might prevent colorectal cancer, but researchers suspect its antioxidant properties – like those found in apple skins – could explain its apparent powers. The drug targets the buildup of uric acid, which contributes to gout, a painful inflammatory disease that causes a condition similar to arthritis.

The enzyme, they found, also causes excessive oxidation, which leads to damage to the DNA and then, possibly, cancer. Alopurinol, they said, functions as a powerful antioxidant that prevents damage to the cell and tissue caused by the existence of oxygen free radicals in the body.

“We have no knowledge about what this drug could do to healthy people without elevated levels of uric acid, but it’s been in use for many years,” Rennert told Reuters Health. “The number of people who have used it is very high and I can’t recall any major side effect.”

The study was limited and showed only a connection between use of the drug and lower colorectal cancer rates, not a direct cause-and-effect relationship, Rennert said. “It only raises the suggestion that this is an interesting alley to investigate further. But it looks pretty promising.”

The researchers took into account known risk factors for colorectal cancer, family history, ethnic origin, as well as risk-reducing factors such as the amount of vegetables in diet, physical activity, and the taking of aspirin or other non-steroidal anti-inflammatory drugs on a regular basis.