The Application of Fluoxetine and Its Related Medicines in Brain Tumor Treatment

Primary brain tumors are tumors that start in the brain. There are many types and subtypes of primary brain tumors. Examples include gliomas, meningomas, medullablastomas, pituitary adenomas, and central nervous system lymphomas. Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor in adults and accounts for about 50% to 60% of cases. Besides, metastatic brain tumors occur in about one-fourth of all cancers that spread through the body. They are much more common than primary brain tumors and occur in 10 - 30% of adult cancers. The standard approach for treating brain tumors is to reduce the tumor as much as possible using surgery, radiotherapy or chemotherapy. Such treatments are used alone or, more commonly, in combination with one another. The intensity, combination, and sequence of treatments depend on the brain tumor type, its size and location, and patient age, health status, and medical history. In general, chemotherapy for brain tumors is usually administered following surgery or radiation therapy. The reason why chemotherapy is not an effective initial treatment for brain tumors is because most standard drugs cannot pass the blood-brain barrier (BBB). Efficacy of the chemotherapy is impeded by insufficient drug delivery across the BBB. Unfortunately, limited medications which are able to pass through the BBB cannot discern efficiently between healthy and cancerous cells, thus causing side effects. A drug which can pass through BBB and selectively kill brain tumor cells has been highly anticipated. A previous epidemiologic study reported a 30% reduced risk of colorectal cancer among users of high doses of serotonin reuptake inhibitor (SSRI) antidepressants. The SSRI antidepressants have been reported to specifically kill malignant cells. Our preliminary data shows that fluoxetine selectively induce glioma cell apoptosis via activating α-amino-3-hydroxy-5-methyl-4-isozazole (AMPA) receptor. However, the therapeutic potential of Fluoxetine, Sertraline, Paroxetine or AMPA receptor potentiator (ARP) for the treatment of GBM or metastatic brain tumors remains unclear. Here we attempted to explore the therapeutic potential of in the treatment of primary brain tumor (GBM) or metastatic brain tumor and to dissect the underlying signaling pathways of 3 SSRIs and ARP induced cell death. The aims of this three-year project are: Aims-1st year: (1) Validation of the survival time in GBM patients with or without Sertraline, Paroxetine or AMPA receptor potentiator (ARP) treatment from the National Health Insurance Research Database. (2) Screening for the potential candidate for the treatment of GBM and discovering the mechanism. Aims-2ed year: (1) Validation of the incidence and survival time in metastatic brain tumors patients with or without Sertraline, Paroxetine or AMPA receptor potentiator (ARP) treatment from the National Health Insurance Research Database. (2)Screening for the potential candidate for the treatment of metastatic brain tumors and discovering the mechanism. Aims-3rd year: Phase II clinical trials of potential SSRIs or ARP in GBM patients.