Reversal of P-Glycoprotein and Multidrug-Resistance Protein-Mediated Drug Resistance in KB Cells by 5-O-Benzoylated Taxinine K

  1. Hiroshi Okumura1,
  2. Zhe-Sheng Chen1,
  3. Magoichi Sakou3,
  4. Tomoyuki Sumizawa1,
  5. Tatsuhiko Furukawa1,
  6. Masaharu Komatsu1,
  7. Ryuji Ikeda1,
  8. Hikokazu Suzuki3,
  9. Kosaku Hirota3,
  10. Takashi Aikou2 and
  11. Shin-Ichi Akiyama1
  1. 1Department of Cancer Chemotherapy, Institute for Cancer Research (H.O., Z.-S.C., T.S., T.F., M.K., R.I., S.-I.A.) 2First Department of Surgery (T.A.), Kagoshima University School of Medicine, Kagoshima, Japan; and 3Gifu Pharmaceutical University, Gifu, Japan (M.S., H.S., K.H.)

    Abstract

    A newly synthesized taxoid originally from the Japanese yewTaxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8–5 and KB-C2 cells that overexpress P-gp by directly interacting with P-gp. BTK also moderately reversed the resistance to ADM of KB/MRP cells that overexpress MRP. However, BTK neither inhibited the transporting activity of MRP nor reduced intracellular glutathione levels in KB/MRP cells. BTK shifted the distribution of ADM in KB/MRP cells from punctate cytoplasmic compartments to the nucleoplasm and cytoplasm by inhibiting acidification of cytoplasmic organelles. These two functions of BTK make it able to reverse both P-gp- and MRP-mediated MDR. BTK in combination with ADM should be useful for treating patients with tumors that overexpress both P-gp and MRP.

    Footnotes

    • Send reprint requests to: Dr. Shin-ichi Akiyama, Department of Cancer Chemotherapy, Institute for Cancer Research, Faculity of Medicine, Kagoshima University, 8–35-1 Sakuragaoka Kagoshima 890-8520, Japan. E-mail:akiyamas{at}m3.kufm.kagoshima-u.ac.jp

    • Abbreviations:
      MDR
      multidrug resistance (or resistant)
      P-gp
      P-glycoprotein
      MRP
      multidrug resistance protein
      GSH
      glutathione
      LTC4
      leukotriene C4
      LTD4
      leukotriene D4
      PAK-104P
      2-[4-(diphenylmethyl)-1-piperazinyl]ethyl 5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide
      BTK
      5-O-benzoylated taxinine K
      ADM
      doxorubicin
      VCR
      vincristine
      AO
      acridine orange
      MEM
      minimal essential medium
      APMSF
      p-amidinophenyl methanesulfonyl fluoride hydrochloride
      LRP
      lung resistance-related protein
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      • Received July 17, 2000.
      • Accepted September 13, 2000.
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    1. Molecular Pharmacology December 1, 2000 vol. 58 no. 6 1563-1569
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