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Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system

Archives of Pharmacal Research volume 37, pages 4–15 (2014)Cite this article

Abstract

Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.

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References

  • Abu-Lila, A., T. Suzuki, Y. Doi, T. Ishida, and H. Kiwada. 2009. Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model. Journal of Controlled Release 134: 18–25.

    CAS  PubMed  Article  Google Scholar 

  • Bai, F., C. Wang, Q. Lu, M. Zhao, F.Q. Ban, D.H. Yu, Y.Y. Guan, X. Luan, Y.R. Liu, H.Z. Chen, and C. Fang. 2013. Nanoparticle-mediated drug delivery to tumor neovasculature to combat P-gp expressing multidrug resistant cancer. Biomaterials 34: 6163–6174.

    CAS  PubMed  Article  Google Scholar 

  • Bamias, A., and M.A. Dimopoulos. 2003. Angiogenesis in human cancer: Implications in cancer therapy. European Journal of Internal Medicine 14: 459–469.

    CAS  PubMed  Article  Google Scholar 

  • Beck, A., M.C. Etienne, S. Cheradame, J.L. Fischel, P. Formento, N. Renee, and G. Milano. 1994. A role for dihydropyrimidine dehydrogenase and thymidylate synthase in tumour sensitivity to fluorouracil. European Journal of Cancer 30: 1517–1522.

    Article  Google Scholar 

  • Beck, W.T., M.K. Danks, J.S. Wolverton, R. Kim, and M. Chen. 1993. Drug resistance associated with altered DNA topoisomerase II. Advances in Enzyme Regulation 33: 113–127.

    CAS  PubMed  Article  Google Scholar 

  • Borst, P., R. Evers, M. Kool, and J. Wijnholds. 2000. A family of drug transporters: The multidrug resistance-associated proteins. Journal of the National Cancer Institute 92: 1295–1302.

    CAS  PubMed  Article  Google Scholar 

  • Boyle, P., and B. Levin. 2008. World Cancer Report 2008. Lyon: International Agency for Research on Cancer (IARC), 14–15.

  • Chabner, B.A., and T.G. Roberts. 2005. Timeline: Chemotherapy and the war on cancer. Nature Reviews Cancer 5: 65–72.

    CAS  PubMed  Article  Google Scholar 

  • Chaudhary, A., M.B. Hilton, S. Seaman, D.C. Haines, S. Stevenson, P.K. Lemotte, W.R. Tschantz, X.M. Zhang, S. Saha, T. Fleming, and B. St Croix. 2012. TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types. Cancer Cell 21: 212–226.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Cherian, M.G., A. Jayasurya, and B.H. Bay. 2003. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutation Research 533: 201–209.

    CAS  PubMed  Article  Google Scholar 

  • Chin, J.L., D. Banerjee, S.A. Kadhim, T.E. Kontozoglou, P.J. Chauvin, and M.G. Cherian. 1993. Metallothionein in testicular germ cell tumors and drug resistance. Clinical correlation. Cancer 72: 3029–3035.

    CAS  PubMed  Article  Google Scholar 

  • Choi, C.H. 2005. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell International 5: 30.

    PubMed Central  PubMed  Article  Google Scholar 

  • Choi, H.S., W. Liu, F. Liu, K. Nasr, P. Misra, M.G. Bawendi, and J.V. Frangioni. 2010. Design considerations for tumour-targeted nanoparticles. Nature Nanotechnology 5: 42–47.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Clapper, M.L., S.J. Hoffman, and K.D. Tew. 1990. Sensitization of human colon tumor xenografts to l-phenylalanine mustard using ethacrynic acid. Journal of Cellular Pharmacology 1: 71–78.

    CAS  Google Scholar 

  • Dalton, W.S. 1997. Mechanisms of drug resistance in hematologic malignancies. Seminars in Hematology 34: 3–8.

    CAS  PubMed  Google Scholar 

  • Danenberg, P.V. 1977. Thymidylate synthetase: A target enzyme in cancer chemotherapy. Biochimica et Biophysica Acta 473: 73–92.

    CAS  PubMed  Google Scholar 

  • Davis, M.E., Z.G. Chen, and D.M. Shin. 2008. Nanoparticle therapeutics: An emerging treatment modality for cancer. Nature Reviews Drug Discovery 7: 771–782.

    CAS  PubMed  Article  Google Scholar 

  • Diestra, J.E., G.L. Scheffer, I. Català, M. Maliepaard, J.H. Schellens, R.J. Scheper, J.R. Germà-Lluch, and M.A. Izquierdo. 2002. Frequent expression of the multi-drug resistance associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. Journal of Pathology 198: 213–219.

    CAS  PubMed  Article  Google Scholar 

  • Dietel, M., H. Arps, H. Lage, and A. Niendorf. 1990. Membrane vesicle formation due to acquired mitoxantrone resistance in human gastric carcinoma cell line EPG85–257. Cancer Research 50: 6100–6161.

    CAS  PubMed  Google Scholar 

  • Di Paolo, D., C. Brignole, F. Pastorino, R. Carosio, A. Zorzoli, M. Rossi, M. Loi, G. Pagnan, L. Emionite, M. Cilli, S. Bruno, R. Chiarle, T.M. Allen, M. Ponzoni, and P. Perri. 2011. Neuroblastoma-targeted nanoparticles entrapping siRNA specifically knockdown ALK. Molecular Therapy 19: 1131–1140.

    PubMed  Article  Google Scholar 

  • Doyle, L.A., W. Yang, L.V. Abruzzo, T. Krogmann, Y. Gao, A.K. Rishi, and D.D. Ross. 1998. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America 95: 15665–15670.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Dziegiel, P., J. Forgacz, E. Suder, P. Surowiak, J. Kornafel, and M. Zabel. 2003. Prognostic significance of metallothionein expression in correlation with Ki-67 expression in adenocarcinomas of large intestine. Histology and Histopathology 18: 401–407.

    CAS  PubMed  Google Scholar 

  • Filipowicz, W., L. Jaskiewicz, F.A. Kolb, and R.S. Pillai. 2005. Post-transcriptional gene silencing by siRNAs and miRNAs. Current Opinion in Structural Biology 15: 331–341.

    CAS  PubMed  Article  Google Scholar 

  • Fischel, J.L., M.C. Etienne, T. Spector, P. Formento, N. Renee, and G. Milano. 1995. Dihydropyrimidine dehydrogenase: A tumoral target for fluorouracil modulation. Clinical Cancer Research 1: 991–996.

    CAS  PubMed  Google Scholar 

  • Folkman, J. 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Medicine 1: 27–31.

    CAS  PubMed  Article  Google Scholar 

  • Folkman, J. 2007. Angiogenesis: An organizing principle for drug discovery? Nature Reviews Drug Discovery 6: 273–286.

    CAS  PubMed  Article  Google Scholar 

  • Gao, S., F. Dagnaes-Hansen, E.J. Nielsen, J. Wengel, F. Besenbacher, K.A. Howard, and J. Kjems. 2009. The effect of chemical modification and nanoparticle formulation on stability and biodistribution of siRNA in mice. Molecular Therapy 17: 1225–1233.

    CAS  PubMed  Article  Google Scholar 

  • Gottesman, M.M., T. Fojo, and S.E. Bates. 2002. Multidrug resistance in cancer: Role of ATP dependent transporters. Nature Reviews Cancer 2: 48–58.

    CAS  PubMed  Article  Google Scholar 

  • Gupta, A.K., and M. Gupta. 2005. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26: 3995–4021.

    CAS  PubMed  Article  Google Scholar 

  • Haley, B., and E. Frenkel. 2008. Nanoparticles for drug delivery in cancer treatment. Urologic Oncology 26: 57–64.

    CAS  PubMed  Article  Google Scholar 

  • Hashizume, H., P. Baluk, S. Morikawa, J.W. McLean, G. Thurston, S. Roberge, R.K. Jain, and D.M. McDonald. 2000. Openings between defective endothelial cells explain tumor vessel leakiness. American Journal of Pathology 156: 1363–1380.

    CAS  PubMed  Article  Google Scholar 

  • Hazlehurst, L.A., N.E. Foley, M.C. Gleason-Guzman, M.P. Hacker, A.E. Cress, L.W. Greenberger, M.C. De Jong, and W.S. Dalton. 1999. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Research 59: 1021–1028.

    CAS  PubMed  Google Scholar 

  • Hobbs, S.K., W.L. Monsky, F. Yuan, W.G. Roberts, L. Griffith, V.P. Torchilin, and R.K. Jain. 1998. Regulation of transport pathways in tumor vessels: Role of tumor type and microenvironment. Proceedings of the National Academy of Sciences of the United States of America 95: 4607–4612.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Huwyler, J., A. Cerletti, G. Fricker, A.N. Eberle, and J. Drewe. 2002. By-passing of P-glycoprotein using immunoliposomes. Journal of Drug Targets 10: 73–79.

    CAS  Article  Google Scholar 

  • Izquierdo, M.A., A.G. van der Zee, J.B. Vermorken, P. van der Valk, J.A. Belien, G. Giaccone, et al. 1995. Drug resistance-associated marker Lrp for prediction of response to chemotherapy and prognoses in advanced ovarian carcinoma. Journal of the National Cancer Institute 87: 1230–1237.

    CAS  PubMed  Article  Google Scholar 

  • Jain, R.K. 2005. Antiangiogenic therapy for cancer: Current and emerging concepts. Oncology 19: 7–16.

    PubMed  Google Scholar 

  • Jiang, J., S.J. Yang, J.C. Wang, L.J. Yang, Z.Z. Xu, T. Yang, X.Y. Liu, and Q. Zhang. 2010. Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicin. European Journal of Pharmaceutics and Biopharmaceutics 76: 170–178.

    CAS  PubMed  Article  Google Scholar 

  • Jonston, P.G., H.J. Lenz, and C.G. Leichman. 1995. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumor. Cancer Research 55: 1407–1412.

    Google Scholar 

  • Kanwar, J.R., S.K. Kamalapuram, and R.K. Kanwar. 2011. Targeting survivin in cancer: The cell-signalling perspective. Drug Discovery Today 16: 485–494.

    CAS  PubMed  Article  Google Scholar 

  • Kasahara, K., Y. Fujiwara, K. Nishio, T. Ohmori, Y. Sugimoto, K. Komiya, T. Matsuda, and N. Saijo. 1991. Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Research 51: 3237–3242.

    CAS  PubMed  Google Scholar 

  • Kibria, G., H. Hatakeyama, N. Ohga, K. Hida, and H. Harashima. 2013. The effect of liposomal size on the targeted delivery of doxorubicin to Integrin αvβ3-expressing tumor endothelial cells. Biomaterials 34: 5617–5627.

    CAS  PubMed  Article  Google Scholar 

  • Kickhoefer, V.A., K.S. Rajavel, G.L. Scheffer, W.S. Dalton, R.J. Scheper, and L.H. Rome. 1998. Vaults are up-regulated in multidrug-resistant cancer cell lines. Journal of Biological Chemistry 273: 8971–8974.

    CAS  PubMed  Article  Google Scholar 

  • Kitazono, M., T. Sumizawa, Y. Takebayashi, Z.S. Chen, T. Furukawa, S. Nagayama, A. Tani, S. Takao, T. Aikou, and S. Akiyama. 1999. Multidrug resistance and the lung resistance-related protein in human colon carcinoma SW-620 cells. Journal of the National Cancer Institute 91: 1647–1653.

    CAS  PubMed  Article  Google Scholar 

  • Kondo, Y., E.S. Woo, A.E. Michalska, K.H. Choo, and J.S. Lazo. 1995. Metallothionein null cells have increased sensitivity to anticancer drugs. Cancer Research 55: 2021–2023.

    CAS  PubMed  Google Scholar 

  • Kunjachan, S., A. Blauz, D. Mockel, B. Theek, F. Kiessling, T. Etrych, K. Ulbrich, L.V. Bloois, G. Storm, G. Bartosz, B. Rychlik, and T. Lammers. 2012. Overcoming cellular multidrug resistance using classical nanomedicine formulations. European Journal of Pharmaceutical Sciences 45: 421–428.

    CAS  PubMed  Article  Google Scholar 

  • Laborde, E. 2010. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death and Differentiation 17: 1373–1380.

    CAS  PubMed  Article  Google Scholar 

  • Lenz, H.J., C.G. Leichman, and K.D. Danenberg. 1995. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. Journal of Clinical Oncology 14: 176–182.

    Google Scholar 

  • Linton, K.J. 2007. Structure and function of ABC transporters. Physiology (Bethesda) 22: 122–130.

    CAS  Article  Google Scholar 

  • List, A.F., C.S. Spier, T.M. Grogan, C. Johnson, D.J. Roe, J.P. Greer, S.N. Wolff, H.J. Broxterman, G.L. Scheffer, R.J. Scheper, and W.S. Dalton. 1996. Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia. Blood 87: 2464–2469.

    CAS  PubMed  Google Scholar 

  • Liu, C., G. Zhao, J. Liu, N. Ma, P. Chivukula, L. Perelman, K. Okada, Z. Chen, D. Gough, and L. Yu. 2009. Novel biodegradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. Journal of Controlled Release 140: 277–283.

    CAS  PubMed  Article  Google Scholar 

  • Liu, L.F. 1989. DNA topoisomerase poisons as antitumor drugs. Annual Review of Biochemistry 58: 351–375.

    CAS  PubMed  Article  Google Scholar 

  • Luqmani, Y.A. 2005. Mechanisms of drug resistance in cancer chemotherapy. Medical Principles and Practice 14: 35–48.

    PubMed  Article  Google Scholar 

  • MacDiarmid, J.A., N.B. Amaro-Mugridge, J. Madrid-Weiss, I. Sedliarou, S. Wetzel, K. Kochar, V.N. Brahmbhatt, L. Phillips, S.T. Pattison, C. Petti, B. Stillman, R.M. Graham, and H. Brahmbhatt. 2009. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nature Biotechnology 27: 643–651.

    CAS  PubMed  Article  Google Scholar 

  • Maeda, H., J. Wu, T. Sawa, Y. Matsumura, and K. Hori. 2000. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. Journal of Controlled Release 65: 271–284.

    CAS  PubMed  Article  Google Scholar 

  • Meng, H., M. Liong, T. Xia, Z. Li, Z. Ji, J.I. Zink, and A.E. Nel. 2010. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano 4: 4539–4550.

    CAS  PubMed  Article  Google Scholar 

  • Murakami, M., H. Cabral, Y. Matsumoto, S. Wu, M.R. Kano, T. Yamori, N. Nishiyama, and K. Kataoka. 2011. Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting. Science Translational Medicine 3: 64ra2.

    CAS  PubMed  Article  Google Scholar 

  • Murphy, E.A., B.K. Majeti, L.A. Barnes, M. Makale, S.M. Weis, K. Lutu-Fuga, W. Wrasidlo, and D.A. Cheresh. 2008. Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis. Proceedings of the National Academy of Sciences of the United States of America 105: 9343–9348.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Nakamura, K., A.S. Abu Lila, M. Matsunaga, Y. Doi, T. Ishida, and H. Kiwada. 2011. A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA. Molecular Therapy 19: 2040–2047.

    CAS  PubMed  Article  Google Scholar 

  • Pastorino, F., C. Brignole, D. Marimpietri, M. Cilli, C. Gambini, D. Ribatti, R. Longhi, T.M. Allen, A. Corti, and M. Ponzoni. 2003. Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Research 63: 7400–7409.

    CAS  PubMed  Google Scholar 

  • Patil, Y., and J. Panyam. 2009. Polymeric nanoparticles for siRNA delivery and gene silencing. International Journal of Pharmaceutics 367: 195–203.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Patil, Y.B., S.K. Swaminathan, T. Sadhukha, L. Ma, and J. Panyam. 2010. The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials 31: 358–365.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Patil, Y., T. Sadhukha, L. Ma, and J. Panyam. 2009. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. Journal of Controlled Release 136: 21–29.

    CAS  PubMed  Article  Google Scholar 

  • Peer, D., J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, and R. Langer. 2007. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2: 751–760.

    CAS  PubMed  Article  Google Scholar 

  • Persidis, A. 1999. Cancer multidrug resistance. Nature Biotechnology 17: 94–95.

    CAS  PubMed  Article  Google Scholar 

  • Raaijmakers, H.G., M.A. Izquierdo, H.M. Lokhorst, C. de Leeuw, J.A. Belien, A.C. Bloem, A.W. Dekker, R.J. Scheper, and P. Sonneveld. 1998. Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma. Blood 91: 1029–1036.

    CAS  PubMed  Google Scholar 

  • Rajagopal, A., and S.M. Simon. 2003. Subcellular localization and activity of multidrug resistance proteins. Molecular Biology of the Cell 14: 3389–3399.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Rejman, J., V. Oberle, I.S. Zuhorn, and D. Hoekstra. 2004. Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochemical Journal 377: 159–169.

    CAS  PubMed  Article  Google Scholar 

  • Rezzani, R. 2004. Cyclosporine A and adverse effects on organs: Histochemical studies. Progress in Histochemistry and Cytochemistry 39: 85–128.

    CAS  PubMed  Article  Google Scholar 

  • Ruoslahti, E. 2002. Specialization of tumour vasculature. Nature Reviews Cancer 2: 83–90.

    PubMed  Article  Google Scholar 

  • Saad, M., O.B. Garbuzenko, and T. Minko. 2008. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (London) 3: 761–776.

    CAS  Article  Google Scholar 

  • Salonga, D., K.D. Danenberg, M. Johnson, R. Metzger, S. Groshen, D.D. Tsao-Wei, H.J. Lenz, C.G. Leichman, L. Leichman, R.B. Diasio, and P.V. Danenberg. 2000. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clinical Cancer Research 6: 1322–1327.

    CAS  PubMed  Google Scholar 

  • Scheffer, G.L., A.B. Schroeijers, M.A. Izquierdo, E.A. Wiemer, and R.J. Scheper. 2000. Lung resistance-related protein/major vault protein and vaults in multidrug-resistant cancer. Current Opinion in Oncology 12: 550–556.

    CAS  PubMed  Article  Google Scholar 

  • Sharma, A., E. Mayhew, and R.M. Straubinger. 1993. Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model. Cancer Research 53: 5877–5881.

    CAS  PubMed  Google Scholar 

  • Shen, F., S. Chu, A.K. Bence, B. Bailey, X. Xue, P.A. Erickson, M.H. Montrose, W.T. Beck, and L.C. Erickson. 2008. Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. Journal of Pharmacology and Experimental Therapeutics 324: 95–102.

    CAS  PubMed  Article  Google Scholar 

  • Shimoda, R., W.E. Achanzar, W. Qu, T. Nagamine, H. Takagi, M. Mori, and M.P. Waalkes. 2003. Metallothionein is a potential negative regulator of apoptosis. Toxicological Sciences 73: 294–300.

    CAS  PubMed  Article  Google Scholar 

  • Shintani, Y., M. Ohta, H. Hirabayashi, H. Tanaka, K. Iuchi, K. Nakagawa, H. Maeda, T. Kido, S. Miyoshi, and H. Matsuda. 2003. New prognostic indicator for non-small-cell lung cancer, quantitation of thymidylate synthase by real-time reverse transcription polymerase chain reaction. International Journal of Cancer 104: 790–795.

    CAS  Article  Google Scholar 

  • Siwak, D.R., A.M. Tari, and G. Lopez-Berestein. 2002. The potential of drug-carrying immunoliposomes as anticancer agents. Clinical Cancer Research 8: 955–956.

    CAS  PubMed  Google Scholar 

  • Smith, K., S. Houlbrook, M. Greenall, J. Carmichael, and A.L. Harris. 1993. Topoisomerase IIα coamplification with erbB2 in human primary breast cancer and breast cancer cell lines -relationship to m-AMSA and mitoxantrone sensitivity. Oncogene 8: 933–938.

    CAS  PubMed  Google Scholar 

  • Soma, C.E., C. Dubernet, D. Bentolila, S. Benita, and P. Couvreur. 2000. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Biomaterials 21: 1–7.

    CAS  PubMed  Article  Google Scholar 

  • Sugahara, S., M. Kajiki, H. Kuriyama, and T.R. Kobayashi. 2007. Complete regression of xenografted human carcinomas by a paclitaxel-carboxymethyl dextran conjugate (AZ10992). Journal of Controlled Release 117: 40–50.

    CAS  PubMed  Article  Google Scholar 

  • Takara, K., H. Hatakeyama, G. Kibria, N. Ohga, K. Hida, and H. Harashima. 2012. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy. Journal of Controlled Release 162: 225–232.

    CAS  PubMed  Article  Google Scholar 

  • Tewey, K.M., T.C. Rowe, L. Yang, B.D. Halligan, and L.F. Liu. 1984. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226: 466–468.

    CAS  PubMed  Article  Google Scholar 

  • Toyoda, Y., Y. Hagiya, T. Adachi, K. Hoshijima, M.T. Kuo, and T. Ishikawa. 2008. MRP class of human ATP binding cassette (ABC) transporters: Historical background and new research directions. Xenobiotica 38: 833–862.

    CAS  PubMed  Article  Google Scholar 

  • Walther, W., U. Stein, and H. Lage. 2010. Jet-injection of short hairpin RNA-encoding vectors into tumor cells. Methods in Molecular Biology 629: 123–139.

    PubMed  Google Scholar 

  • Wang, R.B., C.L. Kuo, L.L. Lien, and E.J. Lien. 2003. Structure-activity relationship: Analyses of p-glycoprotein substrates and inhibitors. Journal of Clinical Pharmacy and Therapeutic 28: 203–228.

    CAS  Article  Google Scholar 

  • Wang, Y., S. Gao, W.H. Ye, H.S. Yoon, and Y.Y. Yang. 2006. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nature Materials 5: 791–796.

    CAS  PubMed  Article  Google Scholar 

  • Wang, Z., Y. Li, A. Ahmad, A.S. Azmi, D. Kong, S. Banerjee, and F.H. Sarkar. 2010. Targeting mirnas involved in cancer stem cell and EMT regulation: An emerging concept in overcoming drug resistance. Drug Resistance Updates 13: 109–118.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Wright, J.A., H.S. Smith, F.M. Watt, M.C. Hancock, D.L. Hudson, and G.R. Stark. 1990. DNA amplification is rare in normal human cells. Proceedings of the National Academy of Sciences of the United States of America 87: 1791–1795.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Wu, J., Y. Lu, A. Lee, X. Pan, X. Yang, X. Zhao, and R.J. Lee. 2007. Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. Journal of Pharmacy and Pharmaceutical Sciences 10: 350–357.

    CAS  PubMed  Google Scholar 

  • Yamachika, T., H. Nakanishi, K. Inada, T. Tsukamoto, T. Kato, M. Fukushima, M. Inoue, and M. Tatematsu. 1998. A new prognostic factor for colorectal carcinoma, thymidylate synthase, and its therapeutic significance. Cancer 82: 70–77.

    CAS  PubMed  Article  Google Scholar 

  • Yuan, F., M. Leunig, S.K. Huang, D.A. Berk, D. Papahadjopoulos, and R.K. Jain. 1994. Microvascular permeability and interstitial penetration of sterically stabilized (Stealth®) liposomes in a human tumor xenografts. Cancer Research 54: 3352–3356.

    CAS  PubMed  Google Scholar 

  • Zhang, B., M. Liu, H.K. Tang, H.B. Ma, C. Wang, X. Chen, and H.Z. Huang. 2012. The expression and significance of MRP1, LRP, TOPOIIβ, and BCL2 in tongue squamous cell carcinoma. Journal of Oral Pathology and Medicine 41: 141–148.

    CAS  PubMed  Article  Google Scholar 

  • Zhang, L., F.X. Gu, J.M. Chan, A.Z. Wang, R.S. Langer, and O.C. Farokhzad. 2008. Nanoparticles in medicine: therapeutic applications and developments. Clinical Pharmacology and Therapeutics 83: 761–769.

    CAS  PubMed  Article  Google Scholar 

  • Zhou, S.F. 2008. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 38: 802–832.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This study was supported in parts by grants from the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Nagai Foundation, Tokyo; as well as by a Grant-in-Aid for Research on Medical Device Development from the Ministry of Health, Labour and Welfare of Japan (MHLW).

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  1. Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan

    Golam Kibria, Hiroto Hatakeyama & Hideyoshi Harashima

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Kibria, G., Hatakeyama, H. & Harashima, H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch. Pharm. Res. 37, 4–15 (2014). https://doi.org/10.1007/s12272-013-0276-2

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  • DOI: https://doi.org/10.1007/s12272-013-0276-2

Keywords

  • Cancer multidrug resistance (MDR)
  • Key regulators
  • Drug delivery system
  • Reversal of MDR