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
Publication statusPublished - 1998 Apr 1
Externally publishedYes

Fingerprint

Catalytic RNA
Retinoids
Myeloid Cells
Tretinoin
Restoration
Acute Promyelocytic Leukemia
P-Glycoprotein
Acid resistance
Granulocytes
Drug Resistance
Catalyst activity
Cell Proliferation
Messenger RNA
Recurrence

ASJC Scopus subject areas

  • Hematology

Cite this

Matsushita, H., Kizaki, M., Kobayashi, H., Ueno, H., Muto, A., Takayama, N., ... Ikeda, Y. (1998). Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells. Blood, 91(7), 2452-2458.

Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells. / Matsushita, Hiromichi; Kizaki, Masahiro; Kobayashi, Hiroyuki; Ueno, Hironori; Muto, Akihiro; Takayama, Nobuyuki; Awaya, Norihiro; Kinjo, Kentaro; Hattori, Yutaka; Ikeda, Yasuo.

In: Blood, Vol. 91, No. 7, 01.04.1998, p. 2452-2458.

Research output: Contribution to journalArticle

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, vol. 91, no. 7, pp. 2452-2458.
Matsushita H, Kizaki M, Kobayashi H, Ueno H, Muto A, Takayama N et al. Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells. Blood. 1998 Apr 1;91(7):2452-2458.
Matsushita, Hiromichi ; Kizaki, Masahiro ; Kobayashi, Hiroyuki ; Ueno, Hironori ; Muto, Akihiro ; Takayama, Nobuyuki ; Awaya, Norihiro ; Kinjo, Kentaro ; Hattori, Yutaka ; Ikeda, Yasuo. / Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid- resistant myeloid leukemic cells. In: Blood. 1998 ; Vol. 91, No. 7. pp. 2452-2458.
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