Fluoxetine Inhibits Multidrug Resistance Extrusion Pumps and Enhances Responses to Chemotherapy in Syngeneic and in Human Xenograft Mouse Tumor Models

Abstract

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.

Fluoxetine regulates cell growth inhibition of interferon-α

“…Thus, fluoxetine may help a drug to be sensitive to tumor cells and accumulate to a sufficient level that culminates and undergoes cell growth inhibition (15,27). In addition to our observation in T24 cells, similar results of IFN-α in combination with fluoxetine were observed in human Jurkat-T, Huh7.5 and U2OS cells (data not shown).…”

Antidepressant fluoxetine and its potential against colon tumors

“…These studies have mainly been focused on the antiproliferative effects of FLX treatment in colon tumorigenesis [38,[63][64][65] . In cell culture models, FLX was reported to not only inhibit multidrug resistance and increase the intracellular doxorubicin concentration [66] , but also to induce a further nuclear distribution of this chemotherapeutic drug [67] .…”

“…FLX treatment seems to block tumor growth by breaking the malignant metabolism down [49,[52][53][54][55] . While the pieces for this puzzle are slowly being pulled together, there are already several reports which have given the ground ideas for following investigations [38][39][40]49,50,[52][53][54][55][56]58,60,61,[64][65][66][67][87][88][89][90][91][92]95] . Besides the specific idea of FLX acting against the tumor metabolism, there is an open question regarding the effects of FLX treatment against the "reverse Warburg effect".…”

Effects of desipramine on the cell cycle and apoptosis in Ca3/7 mouse skin squamous carcinoma cells

“…On the other hand, several studies have reported that antidepressants increase the risk of nonHodgkin lymphoma and prostate cancer (5,6), and it is still controversial what effect tricyclic antidepressants have on lung, breast and colon cancer cells (7)(8)(9). Both in vitro and in vivo studies indicate antidepressants are cytotoxic to most malignant cells, particularly colon and breast cancer (10)(11)(12). The induction of apoptosis by DMI has been demonstrated to be significant in colon cancer, glioma and renal tubular cells (13)(14)(15)(16)(17)(18)(19).…”