Reversal of P-glycoprotein and multidrug resistance-associated protein 1 mediated multidrug resistance in cancer cells by HZ08 Isomers, tetrataisohydroquinolin derivatives.
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.
Department of Physiology, China Pharmaceutical University, Nanjing, Jiangsu, P.R. China.
Fang
F
Yan
Yi
Y
Jiang
Yun-Man
YM
Li
Xia
X
Zhen
Juan
J
Cen
Wei-Rong
WR
Fang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D017304:Annexin A5 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D020014:K562 Cells; D020112:Rhodamine 123; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D007546:Isoquinolines; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide; D044005:Tetrahydroisoquinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D020112:Rhodamine 123; D004317:Doxorubicin; D005982:Glutathione Transferase; C022616:thiazolyl blue; D005978:Glutathione; D016650:Fluorescein-5-isothiocyanate