The novel anticancer drug KRN5500 interacts with, but is hardly transported by, human P-glycoprotein

Kohji Takara, Yusuke Tanigawara, Fusao Komada, Kohshi Nishiguchi, Toshiyuki Sakaeda, Katsuhiko Okumura

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


The interaction of the novel anticancer drug KRN5500, a spicamycin derivative, with human P-glycoprotein (P-gp) was analyzed from the viewpoint of cellular pharmacokinetics, i.e. by means of [3H]azidopine photoaffinity labeling, cellular accumulation and transcellular transport experiments. In this study, P-gp-overexpressing LLC-GA5-COL150 cells, porcine kidney epithelial LLC-PK1, cells transformed with human MDR1 cDNA, were used, since this cell line constructs monolayers with tight junctions, and would provide sufficient information far analyzing the cellular pharmacokinetics. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the growth-inhibitory effect of KRN5500 in LLC-GA5-COL150 cells was comparable to that in LLC-PK1 cells (IC50 = 79.4 and 72.7 nM, respectively), but the inhibition of [3H]azidopine binding by KRN5500 was concentration-dependent in the membrane fraction of LLC-GA5-COL150 cells. The cellular accumulation of [14C]KRN5500 after its basal application in LLC-GA5-COL150 cells was slightly lower than that in LLC-PK1 cells, and was restored by the multidrug resistance (MDR) modulator SDZ PSC 833. The basal-to-apical transport of [14C]KRN5500 in LLC-GA5- COL150 cells was also slightly higher than that in LLC-PK, cells, and was inhibited by SDZ PSC 833. However, the basaI-to-apical transport of [14C]KRN5500 in LLC-GA5-COL150 cells was only a little higher than the apical-to-basal transport. Consequently, these results demonstrated that KRN5500 interacted with, but was hardly transported via, P-gp. These observations suggested that KRN5500 may be useful even for the treatment of tumors exhibiting P-gp-mediated MDR.

Original languageEnglish
Pages (from-to)248-254
Number of pages7
JournalJapanese Journal of Cancer Research
Issue number2
Publication statusPublished - 2000 Feb


  • Cellular pharmacokinetic analysis
  • KRN5500
  • Multidrug resistance
  • P-Glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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