ATP-dependent uptake of anti-neoplastic agents by acidic organelles

Yoshinori Moriyama, Tsukasa Manabe, Tamotsu Yoshimori, Yutaka Tashiro, Masamitsu Futai

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Daunomycin, an anti-neoplastic agent, is known to be sequestered by acidic organelles in normal and multidrug-resistant cells [Willingham, M.C., Cornwell, M.M., Cardarelli, C.O., Gottesman, M.M., & Pastan, I. (1986) Cancer Res. 46, 5941-5946]. We studied the mechanism of accumulation of daunomycin into acidic organelles using chromaffin granule vesicles and proteoliposomes reconstituted with purified F-type H+-ATPase as model systems. Radiolabeled daunomycin was taken up by chromaffin vesicles upon addition of ATP. Its ATP-dependent uptake was stimulated about 1.4- to 1.8-fold by valinomycin plus K+, but was inhibited by ammonium chloride (10 mM) and nigericin plus K+. Quinidine (5μM), verapamil (5 μM), or vanadate (0.5 mM), inhibitors of P-glycoprotein, had no effect on its uptake. Daunomycin was also taken up by liposomes reconstituted with F-type H+-ATPase. Furthermore, doxorubicin and vinblastine were taken up by these vesicles, whereas colchicine and rhodamine 123 were not. The accumulations of daunomycin and doxorubicin in acidic organelles of cultured cells were decreased by inhibiting vacuolar ATPase by addition of bafilomycin A, or concanamycin A, or by increasing the internal ΔpH by addition of nigericin. Melittin and N-(6-aminohexyl)-5-chloro-l-naphthalenesulfonamide dissipated the dpH and inhibited accumulation of daunomycin in the membrane vesicles and acidic organelles in cultured cells. These results indicate that the ΔpH established by vacuolartype ATPase drives the uptake of daunomycin, doxorubicin or vinblastine into acidic organelles, and that no specific transporters are involved in their uptakes.

Original languageEnglish
Pages (from-to)213-218
Number of pages6
JournalJournal of Biochemistry
Volume115
Issue number2
Publication statusPublished - Feb 1994
Externally publishedYes

    Fingerprint

Keywords

  • Acidic organelles
  • Daunomycin
  • Multidrug resistance
  • P-glycoprotein
  • Vacuolar ATPase

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging
  • Molecular Biology
  • Biochemistry

Cite this

Moriyama, Y., Manabe, T., Yoshimori, T., Tashiro, Y., & Futai, M. (1994). ATP-dependent uptake of anti-neoplastic agents by acidic organelles. Journal of Biochemistry, 115(2), 213-218.