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[Reversal of multidrug-resistance in human leukemia cell line K562/A02 by a cyclosporin D analogue PSC 833].

AbstractOBJECTIVE:
To explore the efficacy of PSC 833 on multidrug resistance (MDR) reversal and its mechanism.
METHODS:
Human erythroleukemic cell line K562 and its doxorubicin-resistant counterpart K562/A02 were used in the study. Cytotoxicity was assessed by MTT assay, P-gp expression by direct immunofluorescence and mdr1 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR) with beta-actin as internal control. Intracellular DNR retention was measured with flow cytometry.
RESULTS:
K562/A02 cells displayed high levels of mdr1 mRNA and P-glycoprotein and reduced DNR retention compared to their parental K562 cells. 1 micromol/L of PSC 833 had no effect on the levels of mdr1 mRNA and P-gp expression in K562/A02 cells (P > 0.05). PSC 833 conferred a dose-dependent increase on chemosensitivity of K562/A02 to DNR, and its effect was at least 3-fold more potent than that of CsA or Ver. PSC 833 could increase DNR retention in K562/A02 cells. A 100.9% restoration of intracellular DNR retention of the level of K562 cells was gained by PSC 833 at 1.0 micromol/L in K562/A02 cells, whereas only a 86.9% restoration of DNR retention was obtained by CsA at 10 micromol/L in the K562/A02 cells. No effect on DNR sensitivity and retention was found in K562 cells (P > 0.05).
CONCLUSION:
PSC 833 is at least 3 approximately 10 fold more potent than CsA or Ver with respect to MDR reversing activity, and it may function by inhibiting the function of P-gp and not reducing the levels of mdr1 mRNA and P-gp directly.
AuthorsHui Dai, Shaokai Luo, Aihua Yin, Aihua Peng
JournalZhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi (Zhonghua Xue Ye Xue Za Zhi) Vol. 23 Issue 1 Pg. 23-6 (Jan 2002) ISSN: 0253-2727 [Print] China
PMID12015084 (Publication Type: Journal Article)
Chemical References
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcium Channel Blockers
  • Cyclosporins
  • RNA, Messenger
  • Cyclosporine
  • Verapamil
  • valspodar
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (drug effects, genetics, metabolism)
  • Calcium Channel Blockers (pharmacology)
  • Cyclosporine (pharmacology)
  • Cyclosporins (pharmacology)
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Humans
  • K562 Cells (cytology, drug effects, metabolism)
  • RNA, Messenger (drug effects, genetics, metabolism)
  • Verapamil (pharmacology)

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