Skip to main content

Advertisement

SpringerLink
Log in

Fluoxetine synergys with anticancer drugs to overcome multidrug resistance in breast cancer cells

  • Research Article
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Baguley BC. Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 2010;46:308–16.

    Article  CAS  PubMed  Google Scholar 

  2. Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc). 2000;65:95–106.

    CAS  Google Scholar 

  3. O'Connor R. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance. Curr Cancer Drug Targets. 2009;9:273–80.

    Article  PubMed  Google Scholar 

  4. Borst P, Jonkers J, Rottenberg S. What makes tumors multidrug resistant? Cell Cycle. 2007;6(22):2782–7.

    Article  CAS  PubMed  Google Scholar 

  5. Shi X, Liu S, Kleeff J, Friess H, Buchler MW. Acquired resistance of pancreatic cancer cells towards 5-fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology. 2002;62:354–62.

    Article  CAS  PubMed  Google Scholar 

  6. Rathinasamy K, Jindal B, Asthana J, Singh P, Balaji PV, Panda D. Griseofulvin stabilizes microtubule dynamics, activates p53 and inhibits the proliferation of MCF-7 cells synergistically with vinblastine. BMC Cancer. 2010;10:213.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Saha MN, Micallef J, Qiu L, Chang H. Pharmacological activation of the p53 pathway in haematological malignancies. J Clin Pathol. 2010;63(3):204–9.

    Article  CAS  PubMed  Google Scholar 

  8. Takeba Y, Sekine S, Kumai T, Matsumoto N, Nakaya S, Tsuzuki Y, et al. Irinotecan-induced apoptosis is inhibited by increased P-glycoprotein expression and decreased p53 in human hepatocellular carcinoma cells. Biol Pharm Bull. 2007;30(8):1400–6.

    Article  CAS  PubMed  Google Scholar 

  9. Desoise B. Anticancer drug resistance and inhibition of apoptosis. Anticancer Res. 1994;14:2291–4.

    Google Scholar 

  10. Bush JA, Li G. Cancer chemoresistance: the relationship between P53 and multidrug transporters. Int J Cancer. 2002;98:323–30.

    Article  CAS  PubMed  Google Scholar 

  11. Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW. Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene. 2004;23(16):2934–49.

    Article  CAS  PubMed  Google Scholar 

  12. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist. 2003;8:411–24.

    Article  CAS  PubMed  Google Scholar 

  13. Kuo MT. Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol. 2007;608:23–30.

    Article  CAS  PubMed  Google Scholar 

  14. Massie MJ, Holland JC. Depression and the cancer patient. J Clin Psychiatry. 1990;51:12–7.

    PubMed  Google Scholar 

  15. Cheer SM, Goa KL. Fluoxetine. A review of its therapeutic potential in the treatment of depression with physical illness. Drugs. 2001;61:81–110.

    Article  CAS  PubMed  Google Scholar 

  16. Razavi D, Allilaire JF, Smith M, Salimpour A, Verra M, Desclaux B, et al. The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand. 1996;94(3):205–10.

    Article  CAS  PubMed  Google Scholar 

  17. Navari RM, Brenner MC, Wilson MN. Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy. Breast Cancer Res Treat. 2008;112:197–201.

    Article  CAS  PubMed  Google Scholar 

  18. Peer D, Dekel Y, Melikhov D, Margalit R. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Cancer Res. 2004;64:7562–9.

    Article  CAS  PubMed  Google Scholar 

  19. Choi MR, Oh DH, Kim SH, Yang BH, Lee JS, Choi J, et al. Fluoxetine up-regulates bcl-xL expression in rat c6 glioma cells. Psychiatry Investig. 2011;8:161–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fumagalli F, Molteni R, Calabrese F, Frasca A, Racagni G, Riva MA. Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain. J Neurochem. 2005;93:1551–60.

    Article  CAS  PubMed  Google Scholar 

  21. Leonard GD, Polgar O, Bates SE. ABC transporters and inhibitors: new targets, new agents. Curr Opin Invest Drugs. 2002;3:1652–9.

    CAS  Google Scholar 

  22. Kars MD, Işeri OD, Gunduz U, Molnar J. Reversal of multidrug resistance by synthetic and natural compounds in drug-resistant MCF-7 cell lines. Chemotherapy. 2008;54:194–200.

    Article  CAS  PubMed  Google Scholar 

  23. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol. 1995;48:1407–12.

    Article  CAS  PubMed  Google Scholar 

  24. Freire-Garabal M, Núñez MJ, Pereiro D, Riveiro P, Losada C, Fernández-Rial JC, et al. Effects of fluoxetine on the development of lung metastases induced by operative stress in rats. Life Sci. 1998;63:31–8.

    Article  Google Scholar 

  25. Peer D, Margalit R. Fluoxetine and reversal of multidrug resistance. Cancer Lett. 2006;237:180–7.

    Article  CAS  PubMed  Google Scholar 

  26. Argov M, Kashi R, Peer D, Margalit R. Treatment of resistant human colon cancer xenograftsby a fluoxetine–doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett. 2009;274:118–25.

    Article  CAS  PubMed  Google Scholar 

  27. Ong JC, Sun F, Chan E. Development of stealth liposome coencapsulating doxorubicin and fluoxetine. J Liposome Res. 2011;21(4):261–71.

    Article  CAS  PubMed  Google Scholar 

  28. Serafeim A, Holder MJ, Grafton G, Chamba A, Drayson MT, Luong QT, et al. Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells. Blood. 2003;101(8):3212–9.

    Article  CAS  PubMed  Google Scholar 

  29. Cloonan SM, Williams DC. The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt’s lymphoma. Int J Cancer. 2011;128:1712–23.

    Article  CAS  PubMed  Google Scholar 

  30. Hait WN. JM Yang. The individualization of cancer therapy: the unexpected role of p53. Trans Am Clin Climatol Assoc. 2006;117:85–101.

    PubMed  PubMed Central  Google Scholar 

  31. Lee CS, Kim YJ, Jang ER, Kim W, Myung SC. Fluoxetine induces apoptosis in ovarian carcinoma cell line OVCAR-3 through reactive oxygen species-dependent activation of nuclearfactor-kappaB. Basic Clin Pharmacol Toxicol. 2010;106:446–53.

    Article  CAS  PubMed  Google Scholar 

  32. Djordjevic J, Djordjevic A, Adzic M, Elaković I, Matić G, Radojcic MB. Fluoxetine affects antioxidant system and promotes apoptotic signaling in Wistar rat liver. Eur J Pharmacol. 2011;659:61–6.

    Article  CAS  PubMed  Google Scholar 

  33. Frick LR, Rapanelli M, Arcos ML, Cremaschi GA, Genaro AM. Oral administration of fluoxetine alters the proliferation/apoptosis balance of lymphoma cells and up-regulates T cell immunity in tumor-bearing mice. Eur J Pharmacol. 2011;659:265–72.

    Article  CAS  PubMed  Google Scholar 

  34. Liu F, Xie ZH, Cai GP, Jiang YY. The effect of survivin on multidrug resistance mediated by P-glycoprotein in MCF-7 and its adriamycin resistant cells. Biol Pharm Bull. 2007;30(12):2279–83.

    Article  CAS  PubMed  Google Scholar 

  35. Cen J, Qi Y, Tao YF, Deng Y, Fang WR, Li YM, et al. HZ08, A great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM. Eur J Pharmacol. 2010;647:21–30.

    Article  CAS  PubMed  Google Scholar 

  36. Hegedus T, Orfi L, Seprodi A, Varadi A, Sarkadi B, Keri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta. 2002;1587:318–25.

    Article  CAS  PubMed  Google Scholar 

  37. Barbey JT, Roose SP. SSRI safety in over dose. J Clin Psychiatry. 1998;59:42–8.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This project sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. [2010] 609).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Ting Zhou, Jingjing Duan, Yan Wang, Xin Chen, Ganping Zhou & Rongkan Wang

  2. Cancer Center, Sun Yat-Sen University, Guangzhou, 510080, China

    Liwu Fu

  3. Fengxian Hospital, Southern Medical University, Shanghai, 201400, China

    Ting Zhou & Feng Xu

Authors
  1. Ting Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jingjing Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ganping Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rongkan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liwu Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Feng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feng Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhou, T., Duan, J., Wang, Y. et al. Fluoxetine synergys with anticancer drugs to overcome multidrug resistance in breast cancer cells. Tumor Biol. 33, 1299–1306 (2012). https://doi.org/10.1007/s13277-012-0377-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-012-0377-4

Keywords

Search

Navigation