Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Abstract
Multidrug resistance (MDR) is the main obstacle in breast cancer chemotherapy, a reversal reagent with high reversal effect but low toxicity is the hotpot issue at present. The antidepressant fluoxetine (FLX) is a new highly effective chemosensitizer; however, the possible mechanism of FLX in reversal of MDR is unclear. In this study, the effect of FLX on MDR mediated by apoptosis was researched in resistant/sensitive breast cancer cells, which treated by FLX/adriamycin (ADM)/paclitaxel (PTX) alone or FLX-ADM, FLX-PTX combination. Apoptosis assay demonstrated that FLX combined with ADM enhanced the proportion of apoptosis remarkably in MCF-7/ADM but not MCF-7 cells; however, increased the apoptosis rates in both cells when FLX-PTX combination. Results of apoptosis proteins assay showed a upgrade of p53 and a downgrade of Bcl-2 level by FLX-ADM or FLX-PTX combinations in both cells. Our findings indicated that by synergism with anticancer drugs, FLX modulation of apoptosis via targeting p53 and Bcl-2 expression, FLX reverse the breast cancer cell's resistance and enhance the chemosensitivity to ADM and PTX.
PMID:
22549660
[PubMed - as supplied by publisher]
Reprod Toxicol. 2012 Apr 14. [Epub ahead of print] In vivo and in vitro estrogenic activity of the antidepressant fluoxetine.
1: Cancer Biol Ther. 2008 Oct;7(10):1685-93. Epub 2008 Oct 22.Links Fluoxetine inhibits the extracellular signal regulated kinase pathway and suppresses growth of cancer cells.
Stepulak A, Rzeski W, Sifringer M, Brocke K, Gratopp A, Kupisz K, Turski L, Ikonomidou C.
Department of Pediatric Neurology, Children's Hospital, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Dresden, Germany. andrzej.stepulak@uniklinikum-dresden.de
Fluoxetine (FLX) is a widely prescribed antidepressant. Concerns were raised about the potential impact of FLX on cancer growth, because FLX was shown to promote development of breast cancer in rodents. Here we studied the effect of FLX on tumor growth in lung (A549), colon (HT29), neuroblastoma (SKNAS), medulloblastoma/rhabdomyosarcoma (TE671), astrocytoma (MOGGCCM) and breast (T47D) cancer cells and explored potential mechanisms of its action. In our study, FLX reduced growth of cancer cells in vitro in a concentration dependent manner. The antiproliferative effect of FLX was already evident after 24 hours exposure and more pronounced at 96 hours. We demonstrate that FLX inhibits phosphorylation of ERK1/2 kinases in a time and concentration-dependent manner, followed by reduced phosphorylation of transcription factor c-Myc in A549 and HT29 cells. After treatment with FLX, A549 and HT29 cells demonstrated concentration-dependent decrease in the expression of c-fos, c-jun, cyclin A, cyclin D1, and increased expression of p21(waf1) and p53 genes, which resulted in slowing of the cell cycle progression. We suggest that these changes could be responsible for observed inhibition of cancer cell proliferation during FLX treatment in vitro.
PMID: 18836303 [PubMed - indexed for MEDLINE]
Basic Clin Pharmacol Toxicol. 2009 Dec 29. [Epub ahead of print] Fluoxetine Induces Apoptosis in Ovarian Carcinoma Cell Line OVCAR-3 Through Reactive Oxygen Species-Dependent Activation of Nuclear Factor-kappaB.
Lee CS, Kim YJ, Jang ER, Kim W, Myung SC.
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea.
The apoptotic effect of fluoxetine (FLX), an antidepressant, against human epithelial ovarian cancer cell lines OVCAR-3 and SK-OV-3 was investigated in relation to the mitochondria-mediated cell death process and nuclear factor (NF)-kappaB activation. FLX-induced mitochondrial membrane permeability change and formation of reactive oxygen species, leading to cell death. FLX-induced increase in mitochondrial Bax levels, decrease in cytosolic Bid and Bcl-2 levels, loss of the mitochondrial transmembrane potential, cytochrome c release, caspase-3 activation and up-regulation of p53. Oxidant scavengers and Bay 11-7085 [an inhibitor of nuclear factor kappaB (NF-kappaB) activation] prevented the FLX-induced cell death, increase in phosphorylated inhibitory kappaB-alpha and NF-kappaB p65 levels, and binding of NF-kappaB p65 to DNA. Results from this study suggest that FLX may exhibit apoptotic effect against ovarian cancer cell lines by inducing the mitochondrial membrane permeability change, which leads to cytochrome c release and subsequent caspase-3 activation, through reactive oxygen species-dependent activation of NF-kappaB.
PMID: 20050848 [PubMed - as supplied by publisher]
1: Cancer Lett. 2009 Feb 8;274(1):118-25. Epub 2008 Oct 11.Links Treatment of resistant human colon cancer xenografts by a fluoxetine-doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen.
Argov M, Kashi R, Peer D, Margalit R.
Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel. Pre-clinical studies of multidrug resistance (MDR) usually address severe resistance, yet moderate MDR is already clinically-impeding. The purpose of this study was to characterize moderate drug resistance in human colon cancer, and it's modulation by fluoxetine. In vitro fluoxetine enhanced doxorubicin's cytotoxicity (10-fold), increased doxorubicin's intracellular accumulation (32%) and decreased efflux of intracellular doxorubicin (70%). In vivo, mild treatment with a doxorubicin-fluoxetine combination slowed-down tumor progression significantly (p<0.001 vs. doxorubicin alone), comparable to aggressive treatment with bevacizumab. Collectively, our results suggest that combinations of fluoxetine with chemotherapeutic drugs (P-glycoprotein substrates) are worthy of further pursuit for moderate MDR in the clinic.
PMID: 18851896 [PubMed - indexed for MEDLINE
Prozac: Not Just For Depression
25 Dec 2008 http://www.medicalnewstoday.com/articles/133784.php
Prozac is regularly prescribed to ease the emotional pain of patients who are being treated for cancer. But can this common anti-depressant help to fight cancer itself?
Dr. Dan Peer of the Department of Cell Research and Immunology at Tel Aviv University is proving that it can. A study he and his colleagues recently completed validates that Prozac (chemical name fluoxetine) dramatically enhances the effectiveness of a widely used anti-cancer drug. "The good news is that the medical community won't have to wait - Prozac can be used for this purpose right away," says Dr. Peer, noting that doctors in the U.S. already prescribe it to treat depression in chemotherapy patients.
Fighting Drug Resistance in Colon Cancer Patients "Prozac is a very interesting non-specific blocker of cancer resistance," says Dr. Peer, whose study focused on colon cancer and the anti-cancer drug doxorubicin.
In their laboratory experiments, the Tel Aviv University scientists led by graduate student Mirit Argov together with Prof. Rimona Margalit, found that Prozac enhanced doxorubicin's efficacy more than 1,000%. Prozac, in effect, worked to block the cancer drug from leaving the interior of the cancer cell and poisoning the healthy non-cancerous cells that surrounded it.
In animal models, a mild doxorubicin-fluoxetine treatment combination slowed down tumor progression significantly. These results suggest that pairing Prozac with chemotherapeutic drugs to curb drug resistance warrants further clinical study, says Dr. Peer. His research was just published in Cancer Letters, and his suggestions are now listed as recommendations in the latest version of Cancer Encyclopedia.
Working Backward to Make Great Advances
"Working with a major drug developer, we have validated Prozac's potential, and now Tel Aviv University can lead a humanitarian effort to save lives around the globe," he says.
Since it is very hard to protect this patent since any clinician can prescribe Prozac, it is impossible for Tel Aviv University to commercialize its research, says Dr. Peer. Instead, he suggests that researchers join forces internationally to implement retrospective studies of all the types of cancer treatment in which Prozac was prescribed. And further clinical experiments to validate the use of Prozac with chemotherapy is also needed, he stresses.
"The next step is to take the files of chemo patients and determine whether they received Prozac for their depression," says Dr. Peer. "This will streamline the understanding in the scientific community of whether, how and for which cancer-fighting drugs Prozac can be an effective partner. It will also give us invaluable information on how to design new drugs."
Dr. Peer's Tel Aviv University lab is also developing several new drug delivery nanotechnologies to bring novel therapeutics into breast, blood, pancreatic and brain cancers. A recent technological breakthrough to reprogram immune cells involved in ulcerative colitis and Crohn's disease was reported in Science earlier this year and it is the basis of a new platform technology developed in his group.
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