Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells

Hiromichi Matsushita, Masahiro Kizaki, Hiroyuki Kobayashi, Hironori Ueno, Akihiro Muto, Nobuyuki Takayama, Norihiro Awaya, Kentaro Kinjo, Yutaka Hattori, Yasuo Ikeda

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Complete remission is achieved in a high proportion of patients with acute promyelocytic leukemia (APL) after all-trans retinoic acid (RA) treatment, but most patients relapse and develop RA-resistant APL. We have previously reported that both RA-resistant HL-60 (HL-60R) and APL cells express P-glycoprotein and MDR1 transcripts; and these cells differentiate to mature granulocytes after culture with RA and P-glycoprotein antagonist. Ribozymes have been shown to be able to intercept a target RNA by catalytic activity. To address the role of MDR1 in overcoming RA-resistance in APL cells, we investigated the biologic effects of ribozymes against the MDR1 transcript in HL-60R cells. These ribozymes efficiently cleaved MDR1 mRNA at a specific site in vitro. The 196 MDR1 ribozyme was cloned into an expression vector, and stably transfected (HL-60R/196Rz) cells were obtained. Expression of MDR1 transcripts was decreased in HL-60R/196Rz cells compared with parental HL-60R and empty vector-transfected (HL-60R/neo) cells. Interestingly, RA inhibited cellular proliferation and induced differentiation of HL-60R/196Rz cells in a dose-dependent manner, suggesting reversal of drug resistance in HL-60R cells by the MDR1 ribozyme. These data are direct evidence that P-glycoprotein/MDR1 is responsible in part for acquired resistance to RA in myeloid leukemic cells. The MDR1 ribozyme may be a useful tool for investigating the biology of retinoid resistance and may have therapeutic potential for patients with RA-resistant APL.

Original languageEnglish
Pages (from-to)2452-2458
Number of pages7
JournalBlood
Volume91
Issue number7
DOIs
Publication statusPublished - 1998 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells'. Together they form a unique fingerprint.

  • Cite this

    Matsushita, H., Kizaki, M., Kobayashi, H., Ueno, H., Muto, A., Takayama, N., Awaya, N., Kinjo, K., Hattori, Y., & Ikeda, Y. (1998). Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells. Blood, 91(7), 2452-2458. https://doi.org/10.1182/blood.v91.7.2452