Reversal of P-Glycoprotein and Multidrug Resistance-Associated Protein 1 Mediated Multidrug Resistance in Cancer Cells by HZ08 Isomers, Tetrataisohydroquinolin Derivatives

• Published in: Biological & Pharmaceutical Bulletin Vol. 31; no. 6; pp. 1258 - 1264
• Main Authors: Yan, Fang, Jiang, Yi, Li, Yun-Man, Zhen, Xia, Cen, Juan, Fang, Wei-Rong
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.06.2008; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Annexin A5 - metabolism; Antibiotics, Antineoplastic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Cell Cycle - drug effects; Cell Line, Tumor; DNA, Neoplasm - biosynthesis; DNA, Neoplasm - genetics; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Flow Cytometry; Fluorescein-5-isothiocyanate; Glutathione - metabolism; Glutathione Transferase - metabolism; Humans; HZ08; Isoquinolines - chemistry; Isoquinolines - pharmacology; K562 Cells; multidrug resistance; multidrug resistance protein 1; P-glycoprotein; Rhodamine 123; Tetrahydroisoquinolines - chemistry; Tetrahydroisoquinolines - pharmacology; Tetrazolium Salts; Thiazoles
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.31.1258

Overexpression of P-glycoprotein (Pgp) and multidrug resistance protein 1 (MRP1) by tumors results in multidrug resistance (MDR) to structurally unrelated anti-tumor agents. HZ08, a chiral compound, was a newly synthesized tetraisohydroquinoline derivative to reverse Pgp and MRP1 mediated MDR. In present studies, R, S-HZ08 and their racemate reversed the resistance to adriamycin and vincristine of adriamycin-selected human leukemia (K562/ADM) cells that overexpress Pgp. R, S-HZ08 and their racemate modulated adriamycin cytotoxicity when R, S-HZ08 and their racemate were removed 12 h prior to the cytotoxicity assay. In addition, R, S-HZ08 and their racemate increased intracellular accumulation of Rhodamine123 in Caco-2 cells that overexpress Pgp. Furthermore, using a DNA content analysis and an annexin V binding assay, R, S-HZ08 and their racemate effectively reversed the resistance to adriamycin-induced apoptosis in K562/ADM cells. R, S-HZ08 and their racemate also moderately reversed the resistance to adriamycin and vincristine of MCF-7/ADM cells that overexpress MRP1. However, R, S-HZ08 and their racemate hardly affected intracellular glutathione (GSH) levels and glutathione S-transferase (GST) activities in MCF-7/ADM cells. The result showed that R, S-HZ08 and their racemate possibly reverse MDR1 mediated multidrug resistance by a direct interaction with MRP1, not interaction with MRP1 via GSH. Thus, R, S-HZ08 and their racemate should be useful for treating patients with tumors that overexpress both Pgp and MRP1.