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.
Cancer Res. 2004 Oct 15;64(20):7562-9. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. (PDF attached below)
Peer D, Dekel Y, Melikhov D, Margalit R.
Department of Biochemistry, the George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv, Israel. Multidrug resistance (MDR) operated by extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins, is a major reason for poor responses and failures in cancer chemotherapy. MDR modulators (chemosensitizers) were found among drugs approved for noncancer indications and their derivatives. Yet toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Among newly designed chemosensitizers, some still suffer from toxicity and adverse effects, whereas others progressed to clinical trials. Diversities among tumors and among MDR pumps indicate a need for several clinically approved MDR modulators. Here we report for the first time that fluoxetine (Prozac), the well-known antidepressant, is a highly effective chemosensitizer. In vitro, fluoxetine enhanced (10- to 100-fold) cytotoxicity of anticancer drugs (doxorubicin, mitomycin C, vinblastine, and paclitaxel) in drug-resistant but not in drug-sensitive cells (5 and 3 lines, respectively). Fluoxetine increased drug accumulation within MDR-cells and inhibited drug efflux from those cells. In vivo, fluoxetine enhanced doxorubicin accumulation within tumors (12-fold) with unaltered pharmacokinetics. In four resistant mouse tumor models of both syngeneic and human xenograft, combination treatment of fluoxetine and doxorubicin generated substantial (P < 0.001) improvements in tumor responses and in survivals (2- to 3-fold). Moreover, fluoxetine reversed MDR at doses that are well below its human safety limits, free of the severe dose-related toxicity, adverse effects, and poor solubility that are obstacles to other chemosensitizers. This low-dose range, together with the findings reported here, indicate that fluoxetine has a high potential to join the arsenal of MDR reversal agents that may reach the clinic.
PMID: 15492283 [PubMed - indexed for MEDLINE]
Excerpts from the full article:
The ability of fluoxetine to enhance cytotoxicity for several drugs that differ from one another in mechanism of action and in cellular localization of the site of drug action (5) carries the implication that fluoxetine exerts its beneficial effect in pathways or processes that are independent of the particular mechanism(s) by which each drug causes cell demise.
/
The impact of fluoxetine on tumor responses and on survival was tested in vivo, using five of the cell lines tested in vitro: MCF-7/ADR, B16F10.9, C-26, P388/WT, and P388/ADR. We found common and encouraging trends, as well as in vitro–in vivo correlations, among the results from all of the animal systems, despite the diversities in animal species, tumor models, and measures of tumor response. In lung metastatic disease, the doxorubicin fluoxetine treatment reduced the metastatic burden 4- to 7-fold better than doxorubicin alone, with a corresponding increase in life span (Fig. 5).
/
A chemosensitizer is expected to overturn the poor response of drug-resistant cells to anticancer drugs and at the same time to have little or no effect on drug-sensitive cells (23, 26, 29, 39). Fluoxetine, tested in vitro over the matrix of selected variables, met both expectations. In drug-sensitive cells cytotoxicity generated by a
given drug was unaffected by the presence of fluoxetine in the treatment media (Table 1; Fig. 1B). In drug-resistant cells, acquired and inherent, combination treatment of fluoxetine with an anticancer drug (be it mitomycin C, doxorubicin, vinblastine, or paclitaxel) enhanced cytotoxicity by 2 to 3 orders of magnitude
In solid tumors, the doxorubicin fluoxetine combination generated a 6- to 7-fold reduction in tumor progression (Fig. 7A), with a corresponding increase in life span
...the low-dose range at which fluoxetine was found to modulate MDR in mice and its ability to reverse MDR in human-originating cells (in vitro and in vivo) hold a promise that fluoxetine may reverse MDR in the clinic at doses well below the safe and approved range of 20 to 80 mg/day prescribed for psychiatric therapy (33).
Cancer Lett. 2006 Jun 18;237(2):180-7. Epub 2005 Jul 12. Fluoxetine and reversal of multidrug resistance. (PDF attached)
Peer D, Margalit R.
Department of Biochemistry, George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv 69978, Israel
This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known antidepressant fluoxetine (prozac). The MDR phenomena and mechanisms are discussed, including the roles of ABC transporters as MDR-pumps and the potential involvement of cancer stem cells. The three generations of MDR reversal agents (chemosensitizers) are reviewed, introducing the concept of single-pump and multi-pump agents. The current status of chemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testing novel candidates. Major in vitro and in vivo findings are summarized showing that fluoxetine is a chemosensitizer of the multi-pump type, and proposing it be considered a fourth-generation chemosensitizer. In concluding, we contemplate future prospects of modulating MDR in the clinic.
Breast Cancer Res Treat. 2007 Jan;101(1):113-21. Epub 2006 Nov 18. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.
Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN.
Department of Oncology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN , 55905, USA, goetz.matthew@mayo.edu.
BACKGROUND: Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death. METHODS: Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling. RESULTS: Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007). CONCLUSION: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.
PMID: 17115111 [PubMed - indexed for MEDLINE]
Wait..
Was it the addition of Fluoxetine or the innate metabolism of the patient? Tamoxitest can test for the latter.
Is Mirtazapine And Fluoxetine Helpful In Treating Pancreatic Cancer?
24 Sep 2008
The treatment of pancreatic cancer remains a great challenge. The majority of patients with pancreatic cancer developed major depression. Antidepressant treatment has been accepted as one of the new strategies in cancer adjuvant therapy. However, systemic studies on the treatment of depression in patients with cancer have not been well documented.
A research article published in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Jia Lin evaluated the effectiveness of mirtazapine and fluoxetine on body weight, ingestive behavior, locomotor activity and tumor growth in a pancreatic cancer mouse model in the six-week period trial.
In this study, the researchers observed that mirtazapine had the effectiveness of increasing appetite, partly reversed the rate of weight loss. In addition, the potential effectiveness of weight gain associated with an increase in food intake. However, fluoxetine produced a significant suppression of food intake and promoted weight loss. These effects lasted a long-term. Mirtazapine and fluoxetine didn't affect the pancreatic tumor growth. Mirtazapine had more quickly efficacy on the adaptability to new environment than fluoxetine.
Reference: Jia L, Shang YY, Li YY. Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice. World J Gastroenterol 2008; 14(27): 4377-4382 http://www.wjgnet.com/1007-9327/14/4377.asp
"Excessive Weight Loss
Fluoxetine without dietary restrictions usually results in only a few pounds lost. Sometimes selective serotonin reuptake inhibitors can cause significant weight loss. Patients who have anorexia or malnutrition should be monitored while taking fluoxetine to prevent life threatening complications."
Linear Mode
