Induction of MRP/GS-X pump and cellular resistance to anticancer prostaglandins.

Abstract

We provide evidence that the expression of the human MRP/GS-X pump encoded by the MRP (multidrug resistance associated protein) gene is induced by cisplatin in human leukemia HL-60/R-CP (cisplatin-resistant) cells and modulates cell growth inhibition by delta(7)-prostaglandin A1 (PGA1) methyl ester. The MRP mRNA level in HL-60/R-CP cells increased remarkably after a 24-h incubation with 20 microM cisplatin; interestingly, however, no amplification of the MRP gene was detected. In cisplatin-sensitive HL-60 cells, which express the MRP/GS-X pump at low levels, c-myc expression was substantially suppressed by delta(7)-PGA1 methyl ester and the cell cycle was arrested in G1 phase. By contrast, in HL-60/R-CP cells overexpressing the MRP/GS-X pump, c-myc expression and cell proliferation were much less affected by delta(7)-PGA1 methyl ester. This suggests that induction of the MRP/GS-X pump may confer on cancer cells resistance to anticancer prostaglandins and that the resistance mechanism may involve the increased efflux of PG-glutathione conjugates, as active intermediates, from the cells via the MRP/GS-X pump.

• Authors: K Akimaru, M T Kuo, K Furuta, M Suzuki, R Noyori, T Ishikawa
• Journal: Cytotechnology (Cytotechnology) Vol. 19 Issue 3 Pg. 221-7 ( 1996) ISSN: 0920-9069 [Print] United States
• PMID: 8862010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Multidrug Resistance-Associated Proteins
• Prostaglandins A, Synthetic
• RNA, Messenger
• RNA, Neoplasm
• 9-oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester
• Glutathione
• Cisplatin

Topics

• ATP-Binding Cassette Transporters (biosynthesis, genetics, physiology)
• Antineoplastic Agents (pharmacology)
• Biological Transport (drug effects)
• Cell Division (drug effects)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• G1 Phase (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Genes, myc
• Glutathione (metabolism)
• HL-60 Cells (drug effects, metabolism)
• Humans
• Multidrug Resistance-Associated Proteins
• Polymerase Chain Reaction
• Prostaglandins A, Synthetic (pharmacology)
• RNA, Messenger (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• Structure-Activity Relationship