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Reversal of mdr1-mediated multidrug resistance in human leukemia cells by a new spin-labeled derivative of podophyllotoxin.

Abstract
GP7 (4-[4"-(2", 2", 6", 6"-tetramethyl-l"-piperidinyloxy) amino]-4'-demethyl epipodophyllotoxin) is a promising anticancer drug of the podophyllotoxin class. However, little is known about its anti-multidrug resistance effects. In the present study, we investigated the effects of GP7 on P-glycoprotein (P-gp) overexpression multidrug-resistant human leukemia K562/ADM cells with the comparison of VP-16 and K562 cells. GP7 inhibited the proliferation of K562/ADM cells in a concentration- or time-dependent manner, and the inhibitory effect of GP7 on K562/ADM cells was 1.50-fold higher than that of VP-16. GP7 caused G2/M phase accumulation but VP-16 caused S phase accumulation in K562/ADM and K562 cells. GP7 could induce apoptosis of both K562/ADM and K562 cell lines, but there was no significant difference between GP7- and VP-16-induced apoptotic ratios. GP7 could also induce typical apoptotic morphological changes and internucleosomal DNA fragmentation of K562/ADM and K562 cells, but DNA fragmentation induced by GP7 in K562/ADM cells was weaker than that in K562 cells. When treated with GP7 or VP-16 for 48 h, 128-256 microM GP7 induced more DNA fragmentation than VP-16 did, but 32-64 microM GP7 induced less DNA fragmentation than VP-16 did. GP7 could down-regulate the expression of P-gp in K562/ADM cells but VP-16 could not. Our findings suggest that GP7 may reverse multidrug resistance in human leukemia K562/ADM cells via down-regulation of P-gp expression.
AuthorsShe-Ning Qi, Li-Juan Song, Yan Chen, Yuan-Xue Jing
JournalDie Pharmazie (Pharmazie) Vol. 65 Issue 2 Pg. 117-21 (Feb 2010) ISSN: 0031-7144 [Print] Germany
PMID20225656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • DNA, Neoplasm
  • Spin Labels
  • Tetrazolium Salts
  • Thiazoles
  • thiazolyl blue
  • Podophyllotoxin
Topics
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, biosynthesis, genetics)
  • Antineoplastic Agents, Phytogenic (administration & dosage, therapeutic use)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Cell Division (drug effects)
  • Cell Line, Tumor
  • DNA Fragmentation
  • DNA, Neoplasm (biosynthesis, genetics)
  • Down-Regulation
  • Drug Resistance, Neoplasm (genetics)
  • Electrophoresis, Agar Gel
  • Flow Cytometry
  • G2 Phase (drug effects)
  • Humans
  • K562 Cells
  • Leukemia (drug therapy, pathology)
  • Podophyllotoxin (administration & dosage, analogs & derivatives, therapeutic use)
  • Spin Labels
  • Tetrazolium Salts
  • Thiazoles

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