The well-known antidepressant Prozac (or by its chemical name fluoxetine) functions as a highly effective chemosensitizer, and at a very low dose, in the fight against resistant cancerous tumors.
Prof. Ramona Margalit and PhD student Dan Parr, from the Department of Biochemistry in the Faculty of Life Sciences of Tel Aviv University, recently discovered that the well-known antidepressant Prozac (or by its chemical name Fluoxetine) functions as a highly effective chemosensitizer, and at a very low dose in the fight against resistant cancerous tumors.. the significantly smaller dose From the safe and permitted area in the treatment of depression, and free from severe side effects and toxic hazards.
The research findings, which are published for the first time today, in the October 15th issue of the journal Cancer Research, were obtained in cancerous cell cultures of mammalian origin, and in cancer models in mice, including cancer of human origin.
Treatment using chemotherapy drugs, alone or in combination with a surgical procedure, is one of the main ways to fight cancer. However, despite the rapid progress in the means of treatment and methods for early detection, there are still too many patients for whom the battle against the disease has failed. One of the main reasons for the failure of drug treatment stems from the resistance of most tumors (about 80% of the cases) to a wide variety of anti-cancer drugs, a resistance known as multidrug resistance (MDR). In this mechanism, there is no change in the drug itself, but rather in Supply. In both drug-sensitive and resistant cancers, the drug must penetrate into the cell in order to carry out its killing action. The difference between sensitivity and resistance is that in the sensitive cases, the drug accumulates inside the cell to a level sufficient to kill, while in the resistant cells, the drug that managed to penetrate into the cell does not accumulate in it. In the membranes of the resistant cells there are pumps, some innate and some acquired, that pump the drug out of the cell at a rate and strength significantly greater than the rate at which it enters the cell. As a result, the level of the drug in the resistant cell is very low and far from the killing threshold. The pumps are non-mucous and not only do they pump a large variety of the old drugs , but there is a tangible danger that they will do so - and therefore sabotage the treatment - also with new and future medicines.
The way to overcome multidrug resistance is direct and seemingly simple: stop pumping and thereby allow a sufficient amount of drug to accumulate in the resistant cell, as in the sensitive cell. This process is called chemosensitization and reagents capable of carrying out this procedure are called chemosensitizers.
In reality, it was discovered that the seemingly simple way is not simple at all, not because of the lack of chemosensitizers, but because of the lack of chemosensitizers that can be treated safely in patients. Medicines that were already approved for other (non-cancer) treatments and showed the ability to stop the pumping were found to be the first generation of chemosensitizers, but unfortunately cancer patients cannot be treated with them. This is because the dose range required of these drugs in order to overcome multidrug resistance is much higher than allowed and exceeds the range in which severe and toxic side effects are caused. Chemical studies of the first generation did not lead to a change in the situation and only a few of the new molecules synthesized on the basis of chemical combinatorics reached the first stages of clinical trials.
Thus, after three decades of recognizing and understanding the phenomenon, and three generations of chemosensitizers, multidrug resistance is still a weighty clinical problem with no applicable solution.
Along with the findings that the researchers discovered regarding Prozac, utmost caution is required since the use of Prozac to overcome multidrug resistance has not yet been tested in humans. This examination is required not only to confirm the findings, but also in order to develop an accurate treatment protocol and define the range of doses that will be effective without causing harm. If the results of the studies are confirmed in humans, this will be a breakthrough that will lead to real progress in the fight against cancer, using old drugs approved for use.
About the researchers:
Prof. Ramona Margalit
Prof. Ramona Margalit is a graduate and certified by the Hebrew University in chemistry, and has a doctorate from Tel Aviv University in biochemistry and biophysics. She did her post-doctoral studies in the field of membrane biophysics at the University of California in Los Angeles. Prof. Margalit is a faculty member of the Department of Biochemistry, in the Faculty of Life Sciences at Tel Aviv University, and served as head of the department in 2003-1999. Prof. Margalit has many graduates who completed their second and third degree studies under her guidance, and the oldest of them already occupy senior positions in Israel in academia, in the pharmaceutical and biotechnology industries, and in medical research laboratories. Prof. Margalit's areas of interest are nano-biotechnology, drug carriers and transport processes in biological membranes that cause pathological problems. Over the years, Prof. Margalit invented and developed two technologies - some of which are already anchored in international patents and some of which are in the process of registering patents - to send medicines using nanoparticles capable of targeting the target, one of them in collaboration with the doctoral student Dan Parr. Together with colleagues from other institutions in Israel, Prof. Margalit founded the Israeli Association for Controlled Release of Biomaterials, which is a branch of the International Scientific Association for Controlled Release, and has research ties with medical and biotechnological industries in Israel and around the world. In her research in the field of pathological transport processes, Prof. Margalit focuses on systems that extract chemotherapeutic drugs from cancer cells, thereby causing cancer tumors to become resistant to these drugs, a resistance that is a serious clinical problem. The research efforts were specifically aimed at finding and developing measures to prevent aspiration, which could be used to treat cancer patients so that they would provide an adequate solution to the problem and at the same time would not cause harm to the patient. As part of these studies, Prof. Margallo and PhD student Dan Parr found the additional activity of the antidepressant Prozac to prevent the absorption of chemotherapy drugs from the cancer cell.
Dan Farr
Dan received all of his academic training at Tel Aviv University, in the Faculty of Life Sciences, and did his second and third degree research under the guidance of Prof. Ramona Margalit, in the Department of Biochemistry. His specialization is in the field of biophysics and biochemistry, especially in the biomedical direction focusing on the field of cancer. His research during his doctorate dealt with the development and characterization of drug carriers that are nanoparticles with the ability to precisely target the cancer tumor. During these studies, Dan was exposed to the resistance of malignant tumors to chemotherapy drugs, and together with Prof. Margalit discovered the additional activity of the anti-depressant drug, Prozac, to overcome this resistance. During his doctoral studies, Dan won merit scholarships, the Wolf Prize for doctoral students, international scholarships for participation in conferences, and was invited to give lectures at international conferences and research institutions. Dan is a co-inventor (with Prof. Ramona Margalit) in a number of inventions submitted for patent registration (one of which has already been approved) registered by Tel Aviv University through its economic company.
