Development of analysis for multidrug resistance protein 1 (MRP1) modulator

• Project/Area Number: 23791162
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Gifu University
• Principal Investigator: OZEKI Michio 岐阜大学, 医学部附属病院, 医員 (60444303)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌 / 薬剤反応 / ABC トランスポーター / 多剤耐性関連蛋白質(MRP1) / 薬剤反応性

Research Abstract

Our purpose of research is to clarify the mechanism of anticancer drug resistanceby tumor cells and developing effective resistance modulators. Multidrug resistance can be mediated by overexpression of the multidrug resistance protein 1(MRP1). MRP function as transmembrane efflux pumps, which decrease intracellular drug accumulation, thereby conferring multidrug resistance. One of the ways to overcome MRP1 mediated multidrug resistance is to use an inhibitor to block the function of MRP1. This is called MRP1 modulator. To date, several MRP1 modulator have entered study and clinical trials. Recently, leukotriene receptor antagonist (LTRA) is thought to be one of the MRP1 modulator. We studied effect to overcome drug resistance by LTRA and have developed original candidate medications.In our study duration, we got results as below; The resistance cancer cells was established by two methods. The cells were selected from Jurkat (human leukemia cell line) by chronic exposure to doxorubicin over 2 months and transfection of MRP1cDNA. In the resistant cells, the overexpression of MRP1 resulted from an increased MRPmRNA level transcribed from amplified MRP gene. The dose-response effects of LTRA in the presence or absence of doxorubicin were examined in both drug-sensitive Jurkat and MRP-overexpressing resistant cells. LTRA reversed Jurkat resistance. The fluorescent accumulation analysis revealed a significant increase of fluorescence in resistant Jurkat pre-incubated LTRA. We demonstrated that LTRA modulate MRP1 scientifically by the measurement of intracellular glutathione, ATPase assay, analysis of cell-cycle pathway. The results were important findings for oncologic research. We have written the report now.

Research Products

• [Journal Article] Propranolol as an alternative treatment option for pediatric lymphatic malformation. (2013)
  • Author(s): Ozeki M, Kanda K, Kawamoto N, OhnishiH, Fujino A, Hirayama M, Kato Z, Azuma E, Fukao T, Kondo N
  • Journal Title: Tohoku J Exp Med Volume: 229 Pages: 61-66
  • NAID: 10031143088
  • Peer Reviewed
• [Journal Article] Peripheral blood stem cell transplantation in a significant body weight difference between a smaller donor and a larger recipient: a case report. (2013)
  • Author(s): Funato M, Kaneko H, Sasai H, Kubota K, Ozeki M, Kanda K, Kato Z, Kondo N.
  • Journal Title: Transfus Apher Sci. Volume: 49 Issue: 3 Pages: 504-6
  • DOI: 10.1016/j.transci.2013.01.015
  • Peer Reviewed
• [Journal Article] Paclitaxel-based chemotherapy for aggressive kaposiform hemangioendothelioma of the temporomastoid region: Case report and review of the literature. (2013)
  • Author(s): Funato M, Fukao T, Sasai H, Hori T, Terazawa D, Kanda K, Ozeki M, Mizuta K, Hirose Y, Kaneko H, Kondo N.
  • Journal Title: Head Neck. Volume: 35 Issue: 8 Pages: 258-61
  • DOI: 10.1002/hed.23107
  • Peer Reviewed
• [Journal Article] Propranolol as an Alternative Treatment Option for Pediatric Lymphatic Malformation (2013)
  • Author(s): Ozeki M, Kanda K,Kawamoto N,Ohnishi H,Fujino A,Hirayama M,Kato Z,Azuma E,Fukao T,Kondo N.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 229 Issue: 1 Pages: 61-66
  • DOI: 10.1620/tjem.229.61
  • NAID: 130004460039
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed
• [Journal Article] Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia (2012)
  • Author(s): Kuramitsu M, Matsubara A, Morio T, Takagi M, Toki T, Terui K, RuNan W, Kanno H, Ohga S, Ohara A, Kitoh T, Sugita K, Kudo T, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I
  • Journal Title: Blood Volume: 119 Pages: 2376-84
  • Peer Reviewed
• [Journal Article] Propranolol for intractable diffuse lymphangiomatosis. (2011)
  • Author(s): Ozeki M, Fukao T, Kondo N
  • Journal Title: N Engl J Med Volume: 364 Pages: 1380-2
  • Peer Reviewed
• [Journal Article] Pediatric acute lymphoblastic leukemia mimicking Henoch-Schonlein purpura (2011)
  • Author(s): Funato M, Kaneko H, Kubota K, Ozeki M, Kanda K, Orii K, Kato Z, Fukao T, Kondo N
  • Journal Title: Pediatr Int Volume: 53 Pages: 766-8
• [Journal Article] Successful treatment of pediatric immune thrombocytopenic purpura associated with ulcerative colitis (2011)
  • Author(s): Funato M, Fukao T, Sasai H, Hori T, Terazawa D, Kubota K, Ozeki M, Orii K, Kaneko H, Kondo N
  • Journal Title: Pediatr Int Volume: 53(5) Pages: 771-3
  • Peer Reviewed
• [Journal Article] Extensive gene deletions in Japanese patients with Diamond-Blackfan anemia (2011)
  • Author(s): Kuramitsu M, Matsubara A, Morio T, Takagi M, Toki T, Terui K, RuNan W, Kanno H, Ohga S, Ohara A, Kitoh T, Sugita K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I
  • Journal Title: Blood Volume: (in press) Issue: 10 Pages: 2376-84
  • DOI: 10.1182/blood-2011-07-368662
  • Peer Reviewed
• [Journal Article] Propranolol for intractable diffuse lymphangiomatosis. (2011)
  • Author(s): Ozeki M, Fukao T, Kondo N.
  • Journal Title: N Engl J Med. Volume: Apr 7;364(14) Pages: 1380-1382
  • Peer Reviewed
• [Journal Article] Pediatric acute lymphoblastic leukemia mimicking Henoch-Schönlein purpura. (2011)
  • Author(s): Funato M, Kaneko H, Kubota K, Ozeki M, Kanda K, Orii K, Kato Z, Fukao T, Kondo N.
  • Journal Title: Pediatr Int. Volume: Oct;53(5) Issue: 5 Pages: 766-768
  • DOI: 10.1111/j.1442-200x.2011.03445.x
  • Peer Reviewed
• [Journal Article] Successful treatment of pediatric immune thrombocytopenic purpura associated with ulcerative colitis. (2011)
  • Author(s): Funato M, Fukao T, Sasai H, Hori T, Terazawa D, Kubota K, Ozeki M, Orii K, Kaneko H, Kondo N.
  • Journal Title: Pediatr Int. Volume: Oct;53(5) Issue: 5 Pages: 771-773
  • DOI: 10.1111/j.1442-200x.2010.03308.x
  • Peer Reviewed
• [Journal Article] Reversible cerebrospinal fluid edema and porencephalic cyst, a rare complication of ventricular catheter (2010)
  • Author(s): Ozeki M, Funato M, Teramoto T, Ohe N, Asano T, Kaneko H, Fukao T, Kondo N
  • Journal Title: J Clin Neurosci Volume: 17 Pages: 658-61
  • Peer Reviewed
• [Journal Article] A family having type 2B von Willebrand disease with an R1306W mutation: Severe thrombocytopenia leads to the normalization of high molecular weight multimers. (2010)
  • Author(s): Ozeki M, Kunishima S, Kasahara K, Funato M, Teramoto T, Kaneko H, Fukao T, Kondo N
  • Journal Title: Thromb Res Volume: 125
  • Peer Reviewed