[Rich66]

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.

PMID: 16014320 [PubMed - indexed for MEDLINE]



PDF