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Doi:10.1016/j.canlet.2005.06.003

Fluoxetine and reversal of multidrug resistance aDepartment of Biochemistry, George S. Wise Life Science Faculty, Tel Aviv University, Tel Aviv 69978, Israel bCBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA Received 31 May 2005; accepted 7 June 2005 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 ABCtransporters 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 ofchemosensitization is summarized, pointing-out the need for additional agents and outlining experimental criteria for testingnovel 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 prospectsof modulating MDR in the clinic.
q 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Multidrug resistance (MDR); ABC transporters; Chemosensitizers; Fluoxetine; Chemotherapy 1. Introduction: tumors, multidrug resistance adjuvant and neoadjuvant for operable solid tumors- (MDR) and the ABC superfamily of transporters often fails the patients due to inherent or acquiredmultidrug resistance (MDR) MDR is a multi- This review focuses on recent findings with respect factorial phenomena and the term itself has seen to reversal of multidrug resistance (MDR) by a multiple use. It is used as a general term to describe veteran drug in use for a non-cancerous indication1.
the resistance to many different chemotherapeutic Chemotherapy, a major treatment for cancer patients- drugs, irrespective of the operating mechanisms It primary for leukemias and inoperable solid tumors, is also used, as in the present context, to describe thespecific mechanism operated by extrusion pumps. Inthis case, the same mechanism confers resistance to a * Corresponding author. Tel.: C972 3 640 9822; fax: C972 3 640 wide repertoire of drugs-from among anthracyclines, vinca alkaloids, anthracenes, tubulin polymerizing E-mail address: [email protected] (R. Margalit).
agents and others-that have very little in common with 1 For reviews on the various aspects of MDR in cancer chemotherapy, from the phenomena itself, through its molecular The one common feature among these drugs is a biology aspects to the clinical situation, the reader is referred toseveral recent excellent reviews [1–5].
sufficient degree of lipophilicity-some more and some 0304-3835/$ - see front matter q 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.canlet.2005.06.003 D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 less-that allows the drug to diffuse across cell specificities, yet they function similarly in terms of membranes (influx and efflux). In the case of drug- sensitive tumor cells, as illustrated in influx is It has been long-recognized that clinical MDR expected to be dominant, due to the direction of the appears in two modes, inherent (intrinsic) and driving force (i.e. the electrochemical gradient of the acquired . Extensive investigations into the drug across the cell membrane). In a drug-sensitive origins of each mode shed light on the phenomena, tumor cell the drug can, thus, accumulate to a but complete molecular understanding is still into sufficient level that culminates in cell death the future. Recent findings from the stem cell arena An entirely different situation exists in MDR tumor have direct bearing on the present issues. Among cells, due to over expression of extrusion transporters them: the high levels of ABC transporters, in from the ABC superfamily . As illustrated particular ABCG2 in normal stem cells; the recognition of cancer stem cells; the retention of chemotherapeutic drug out of the cell, reducing ABC transporters in cancer stem cells The intracellular drug doses below lethal thresholds.
presence of cancer stem cells (irrespective of their Among the ABC transporter sub-families that perform minute share in tumors) that intrinsically and in mammalian cells as MDR extrusion pumps, the most consistently over-express ABC transporters, con- prominently proteins identified and investigated are: tributes to, or complicates (depending on the point P-glycoprotein; the multidrug resistance-associated of view) our understanding of cancer biology, drug proteins (MRP) of which the most studied is MRP1; resistance and the inherent vs. acquired modes of MDR. The roles of cancer stem cells in cancer Under a recently-introduced nomenclature ABCB1 recurrence and in drug resistance-intrinsic and replaces p-glycoprotein, MRP1 is named ABCC1 with acquired-needs further studies. It is, however, other MRP’s given consecutive numbers, and MXR is quite clear, that the presence of cancer stem cells and their impact on MDR should become a major these different families of pump proteins is relatively factor in designing strategies of cancer therapy that modest, and there are differences in substrate attempt to overcome drug resistance.
Extrusion
Extrusion
Extrusion
A Drug-sensitive
Extrusion
C Chemo sensitized
B Drug-resistant
Fig. 1. Schematic representation of drug efflux and drug accumulation in drug-sensitive and in drug-resistant tumor cells. (A) A drug-sensitivetumor cell. Drug molecules-D-diffuse across the cell membrane. InfluxOefflux due to the direction of the drug’s electrochemical gradient,allowing sufficient drug accumulation inside the cell. (B) A drug-resistant tumor cell. In addition to drug diffusion across the cell membrane(influx and efflux), intracellular drug is pumped out of the cell by the extrusion pump (represented as the wide gray ribbons), severely reducingthe drug’s intracellular accumulation. (C) A chemosensitized drug-resistant tumor cell. Pumping is reduced/halted, allowing drug to accumulateinside the cells by diffusion alone, similar to the case of a drug-sensitive tumor cell.
D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 The broad specificity, or rather the non-specific verapamil, cyclosporin A and progesterone nature, of the MDR pumps carries the implication that Valid and available until today as in vitro benchmarks MDR is among clinical problems that refuse to for the search and development of new chemosensi- disappear, for a combination of reasons. Any small tizers, dose-related adverse effects and toxicity, in anticancer drug that operates inside the cell is at risk some cases compounded by solubility limitations, of MDR-pump-mediated extrusion from the cell. A prevented their progress into the clinic case in point is imatinib (Gleevec or Glivec), one of Second and third generation chemosensitizers, the new generation of anticancer drugs directed some of which are in clinical trials were against new targets inside the tumor cells .
drawn from chemical derivatization of first-generation Hopes that this drug will not be prone to extrusion molecules and from combinatorial chemistry were muted upon findings that this drug is a substrate designed for the most against ABCB1. Prominent and a partial inhibitor of ABCB1 In addition, examples are VX-710, PSC833, XR9051, XR9576, combination treatments of conventional chemother- apeutic drugs (prone to MDR) together with new anticancer drugs seem to be significantly more generation chemosensitizers are more potent and less toxic than first-generation compounds, yet some are relationship between cancer stem cells and MDR still prone to adverse effects, poor solubility, and while still needs further investigation, as discussed unfavorable changes in pharmacokinetics of the above, adds to the implication that MDR is here to stay. Consequently, while pursuit of anticancer drugs Among chemosensitizers under investigation, that are not substrates of MDR pumps is of high some are single-pump, namely specific to a single priority, continued efforts are also needed to develop type of pump protein. For example, PSC833, XR9576, GF120918, LY335979 and OC144-093(ONT-093) forABCB1 ; MK571 and probenecide forABCC1 ; pheophorbide and FTC for ABCG2 . Other chemosensitizers are multi-pump,namely capable of addressing more than one type of Drug resistance mediated by the extrusion pumps pump protein. For example, verapamil, Cyclosporin A is, essentially, a problem that holds the key to its and MS-209 are chemosensitizers for ABCB1 and resolution. In the most direct and naive view, simply ABCC1 while Biricodar (VX-710) is a chemosensi- arresting the pump action should lead, as illustrated in C, to re-instating drug accumulation inside the The diversity among pump proteins, the well- MDR tumor cell to levels similar to those of a drug- known heterogeneity of cells in a given tumor sensitive tumor cell (A). That, in turn, should (including the cancer stem cells) as well as patient- lead to demise of MDR tumor cells that would be to-patient variability in responses to the same similar to the response of drug-sensitive tumor cells.
treatment-indicates that clinical resolution of MDR Several different names have been given to an will require treatment with more than one chemo- agent capable of pump arrest: chemosensitizer, MDR sensitizer. This realization carries several impli- reversal agent, MDR modulator, pump-inhibitor cations: the search and development of additional (usually specifying the pump protein such as in ‘Pgp chemosensitizers should continue along with the hope inhibitor’). The first three names indicate the desired that chemosensitizers currently in clinical trials will phenomena, while the latter term, pump-inhibitor, succeed all the way to the clinic. Multi-pump implies a specific mechanism of overturning MDR chemosensitizers, if they mature into the clinic, will have distinct self-explanatory advantage over single- The on going search for chemosensitizers that can be applied in the clinic is into its third generation.
Given the above-discussed need for additional First-generation chemosensitizers were found among chemosensitizers, we find it in place to contemplate drugs already approved for other indications, such as what it takes to qualify a candidate molecule as an D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 effective chemosensitizer for which, furthermore, others, have been investigated for additional thera- pump inhibition is the single or major mechanism.
peutic indications, including cancer . The Starting in vitro, we propose that a candidate molecule potential of fluoxetine as an anticancer drug is should meet three criteria, one functional and two inconclusive. Some of the studies indicate fluoxetine (and other SSRI agents) inhibit tumor proliferation The functional criterion is simply cell demise: whereas other studies imply it induces tumor treatment of a given MDR tumor cell line with a promotion . We wish to emphasize the dose combination of the candidate chemosensitizer and a range: when fluoxetine was investigated for its chemotherapeutic drug, should significantly enhance potential as an anticancer drug, it was tested at cell demise, compared to similar treatment with drug doses similar or higher than those used for its The mechanistic criteria are drug efflux and drug This review also examines the potential of accumulation. Incubating MDR cells with a che- fluoxetine in cancer treatment, but not as an anticancer motherapeutic drug, with and without the candidate drug-rather as a chemosensitizer, potentiating tumor chemosensitizer, should result in higher intracellular response to anticancer drugs. On its face, fluoxetine drug accumulation in the latter case. Efflux of a belongs among first-generation chemosensitizers (as chemotherapeutic drug from those MDR cells, defined in Section 2 above) namely drugs approved preferably under unidirectional conditions, should be for other non-cancer indications and found to act as significantly faster in the absence of the chemosensi- MDR modulators. Yet, one critical factor sets tizer candidate, than when it is present. If a candidate fluoxetine apart from other first-generation members chemosensitizer meets all three criteria, there is merit and indicates it may merit a separate category, in expanding the evaluation (for the same triplicate possibly fourth-generation chemosensitizers. As our criteria) in several directions: testing, in the same cell recent findings summarized below will show, line, a battery of drugs drawn from those known to be unlike the first-generation chemosensitizers and substrates of the given MDR pump; testing the battery unlike the activities discussed in the first paragraph of MDR drugs with additional MDR cell lines; testing, of this section, fluoxetine exerts its ability to pending availability and relevant only in the case of chemosensitize MDR cells at low safe doses, well acquired-MDR, parent drug-sensitive cell lines.
Needless to say, comparative studies to knownchemosensitizers, used as benchmarks, can lend further support to evaluation of the candidatemolecule. Several elegant tools for evaluation of Starting with the in vitro triplicate criteria- chemosensitizer-mediated efflux and accumulation cytotoxicity, efflux and accumulation-defined in have been developed making use of probe molecules Section 2 above, fluoxetine was tested in ABCB1/ MDR tumor cells, in ABCC1/MDR tumor cells and in suggest that such probe molecules be considered as drug-sensitive tumor cells. Test drugs were doxor- additional (rather than standalone) valuable tools for ubicin, mitomycin C, paclitaxel and vinblastine examining a candidate chemosensitizer, as they (VIN). The multi-pump chemosensitizers verapamil cannot replace the combination of functional and and cyclosporin A, shown to affect the ABCB1 and mechanistic studies defined above, performed with the ABCC1 proteins, were used as benchmarks.
3.1.1. In vitro criterion 1: cytotoxicity Two measures are useful for evaluation of 3. Fluoxetine as a chemosensitizer of the whether a chemosensitizer candidate meets the in vitro cytotoxicity criterion: IC50, the drugconcentration that generates 50% inhibition of cell Psychotropic drugs, among them antidepressants proliferation which, in the case of MDR, is that are SSRI agents such as fluoxetine (Prozac) and obviously measured in absence and presence of a D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 fixed chemosensitizer-candidate concentration. RF, verapamil and cyclosporin A slowed-down drug the fold change in drug sensitivity, calculated from efflux, usually increasing the time span for complete the ratio of IC50 in absence, to that in presence, of depletion up to 3–5 h Fluoxetine showed a similar trend, extensively slowing-down the efflux, Fluoxetine, verapamil and cyclosporin doses were thereby increasing the time for complete depletion, to kept to the range of 5–20 mM, where these agents the range of 8–12 h, close to that of drug-sensitive themselves did not affect cell viability. Fluoxetine had no effect on the response of drug-sensitive cellsto chemotherapeutic drugs. RF values-obtained for 3.1.3. In vitro criterion 3: drug accumulation the human breast cancer and colon cancer lines Measuring accumulation with actual drugs and MCF7 and HT29 and the mouse leukemia line with the fluorescent substrate Rhodamine-123, the P388/WT-were in the range of 0.9–1.1 for doxor- benchmarks were found to increase intracellular drug accumulation compared to cells exposed to drugs doxorubicin, mitomycin C and paclitaxel, fluox- alone. This effect was found in inherent and acquired etine-induced RF values in the inherent-ABCC1 cell MDR cells, whether the pump-protein was ABCB1 lines PANC-1 (human pancreatic adenocarcinoma) and T98G (human glioblastoma), were in the range marks increased drug accumulation by 0.2–2 fold, fluoxetine acted similarly and was usually 1.4–3.0 benchmarks verapamil- and cyclosporin A, for the fold better than the benchmarks . In cell lines same drugs and cell lines were (for the most) in where the benchmarks increased drug accumulation the range of 2–7 with two exceptions that did not by 1–10 fold, fluoxetine also acted similarly and was 10–100 fold better than the benchmarks [44, Peer and Fluoxetine’s candidacy as a chemosensitizer for Margalit, unpublished data]. Interestingly, chemo- the ABCB1 pump-protein was tested with doxorubi- sensitizer-induced increases in accumulation for cin, mitomycin C and vinblastine, in the following benchmarks and for the fluoxetine were higher in cell lines: B16F10.9 (mouse melanoma), D122 (sub- ABCB1 than in ABCC1 cells. This, however, could line of mouse Lewis lung carcinoma), C-26 (mouse be due to differences in experimental designs and colon carcinoma), NCI/ADR-RES (human breast methodologies, and will require additional studies to determine whether this is a technical or an intrinsic P388/ADR (mouse leukemia). Similar to the ABCC1 cell lines, verapamil-induced (spot tested)RF values were 2–3, and fluoxetine-induced RF values were 40–60 for mitomycin C, 20–70 fordoxorubicin and 15–70 for vinblastine .
Following the in vitro findings, fluoxetine was studied in several syngeneic and nude mouse tumor models, with doxorubicin as the test drug. Several Drug efflux from drug-sensitive cells was rather parameters were unique to these studies: fluoxetine slow. For example, complete depletion of intracellular was given at the low dose of 0.04 mg/kg body which is doxorubicin from MCF7 cells, under unidirectional well below human safety limits; it was administered flux conditions, takes more than 7 h and is unaffected orally in the drinking water; it was given continuously by verapamil or by fluoxetine [Peer and Margalit, from tumor inoculation until termination of the unpublished data]. Drug efflux from inherent and experiment. Most of the efforts were on efficacy, but acquired MDR cells, whether the pump-protein is it was first verified that fluoxetine did not alter the ABCB1 or ABCC1, was found to be rather fast. For drug’s pharmacokinetics, a problem encountered with example, under unidirectional flux conditions it took some previous-generation chemosensitizers Bio- only 1–2 h for complete depletion of such cells from distribution was also tested, showing that while intracellular doxorubicin, mitomycin C, paclitaxel or fluoxetine generated a 12 fold increase in doxorubicin vinblastine . As expected, the benchmarks accumulation in the lung tumors, it had no effect on D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 drug accumulation in liver, spleen and kidneys of the In summary, fluoxetine met all three in vitro C-26 (inherent ABCB1) solid tumor in the footpad of criteria for acting as a chemosensitizer. We BALB/C mice; a B16F10.9 (inherent ABCB1) model emphasize all three, as one criterion alone may of lung metastatic disease in C57BL/6 mice, P388/ be inconclusive. An example is seen in accumu- WT (drug-sensitive) and P388/ADR (acquired lation studies of a model ABCB1-substrate per- ABCB1) models of peritoneal ascites in BDF1 mice; formed for a series of SSRI agents and known two human xenograft models of subcutaneous (flank) chemosensitizers, where fluoxetine was placed in a solid tumors in athymic nude mice-NCI/ADR-RES low-response group . Fluoxetine also acted as a (acquired ABCB1) and PANC-1 (inherent ABCC1).
chemosensitizer in vivo, with relatively good These models provide for experimental designs in vitro-in vivo correlation. The data indicate it testing tumor progression (the syngeneic models) belongs to the category of multi-pump chemosensi- and tumor regression (the human xenograft models).
tizers, showing capability of reversing MDR All models in which the inoculated tumor cells generated by two major pump proteins ABCB1 showed MDR characteristics in vitro, continued to act as such in vivo. In the drug-resistant in vivo to its mechanism of action, the data generated so models, therapeutic responses and survivals of mice far indicates that fluoxetine acts as a pump treated with doxorubicin alone were not different than inhibitor, but future studies are required to control groups treated with saline or fluoxetine alone determine whether this is the only, or a major, mechanism by which fluoxetine modulates MDR.
(P388/WT), therapeutic responses and survival of the Future studies will also show whether fluoxetine’s doxorubicin-treated group were significantly better multi-pump ability is limited to ABCB1 and than the controls, and addition of fluoxetine to the ABCC1, or extends to additional members of the drug treatment was not different than drug alone In all the MDR in vivo models combination treatment of-doxorubicin (by intravenous injectionin all cases, except intraperitoneal injections in the NCI/ADR-RES model) and fluoxetine (orally, asdescried above)-generated therapeutic responses Two aspects, discussed in previous sections of this that were distinctly and significantly different review, stand out when contemplating the future from those generated by control treatments and, prospects of clinical MDR reversal. The need to as already discussed above, treatment with drug provide cancer patients and their physicians with an alone. The combination treatment slowed down arsenal of clinically-approved chemosensitizers that tumor progression (C-26 and P388/ADR models), will address the different MDR pump-proteins. The reduced lung metastatic burden (B16F10.9 model) need to fully understand the involvement of cancer and generated almost-complete tumor regression stem cells in clinical MDR, and whether the same means will suffice to modulate resistance of the cancer combination treatment increased life spans in all cases. Survival was found to increase by 2–3 fold While the early generations of chemosensitizers in the cases where such an evaluation was possible did not progress into approved clinical modalities, in the course of the study (C-26 and the P388/ADR several directions hold promise to improve the models) Survival was even higher in all other situation. One is the direction taken in pursuing models, where termination of the experiment was third-generation chemosensitizers with the required at a time point in which all control and hope that some clinically-approved chemosensitizers drug-alone animals were dead while 50–100% of will emerge from molecules that are currently in the animals receiving combination treatment were clinical trials. Knowledge and understanding of the pump proteins in the arenas of biochemistry, D. Peer, R. Margalit / Cancer Letters 237 (2006) 180–187 molecular biology and theoretical biology is continu- [6] L. Biganzoli, A. Minisini, M. Aapro, A. Di Leo, Chemother- ously increasing. It is anticipated that these strides apy for metastatic breast cancer, Curr. Opin. Obstet. Gynecol.
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Modern Agricultural Practices: a Dilemma of Farmers and Farm Workers’ Health in the Cash Crop Zone in the Maharashtra State. Dhere Amar M. Indira College of Commerce and Science, Pune, India. Javadekar Prahcee P. Indira Institute of Management Studies, Pune, MS, India. Jagtap Mahesh P. Indira College of Commerce and Science, Pune, MS, India. ABSTRACT Modern agriculture practices have

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