Chemosensitizing effects of synthetic curcumin analogs on human multi-drug resistance leukemic cells. (25th January 2016)

• Record Type: Journal Article
• Authors: Mapoung, Sariya; Pitchakarn, Pornsiri; Yodkeeree, Supachai; Ovatlarnporn, Chitchamai; Sakorn, Natee; Limtrakul, Pornngarm
• Is Part Of: Chemico-biological interactions. Volume 244:(2016)
• Page Start: 140
• Page End: 148
• Publication Date: 2016-01-25
• Subjects: Curcumin analogs -- P-gp inhibitor -- Multi-drug resistance -- Leukemia; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2015.12.001
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Curcumin analogs were synthesized and their multi-drug resistance (MDR) reversing properties were determined in human MDR leukemic (K562/Adr) cells. Four analogs, 1, 7- bis -(3, 4-dimethoxy-phenyl)-hepta-1, 6-diene-3, 5-dione (1J ), 2, 6- bis -(4-hydroxy-3-methoxy-benzylidene)-cyclohexanone (2A ), 2, 6- bis -(3, 4-dihydroxy-benzylidene)-cyclohexanone (2F ) and 2, 6- bis -(3, 4-dimethoxy-benzylidene)-cyclohexanone (2J ) markedly increased the sensitivity of K562/Adr cells to paclitaxel (PTX) for 8-, 2-, 8- and 16- folds, respectively and vinblastine (Vin) for 5-, 3-, 12- and 30- folds, respectively. The accumulation of P-gp substrates, Calcein-AM, Rhodamine 123 and Doxorubicin, was significantly increased by1J (up to 6-, 11- and 22- folds, respectively) and2J (up to 7-, 12- and 17- folds, respectively). Besides2A, 2F and2J dramatically decreased P-gp expression in K562/Adr cells. These results could be summarized in the following way. Analog1J inhibited only P-gp function, while2A and2F inhibited only P-gp expression. Interestingly, 2J exerts inhibition of both P-gp function and expression. The combination index (CI) of combination between2J and PTX (0.09) or Vin (0.06) in K562/Adr cells indicated strong synergistic effects, which likely due to its MDR reversing activity. Moreover, these analogs showed less cytotoxicity to peripheral mononuclear cells (human) and red blood cells (human and rat) suggesting the safety of analogs for further animal and clinical studies. Graphical abstract: Highlights: Analogs 1J, 2A, 2F and 2J at non-toxic doses could reverse P-gp-mediated MDR. The MDR reversing property of analog 1J occurs via the inhibition on P-gp function. The analogs 2A and 2F only inhibit P-gp expression. The analog 2J exerts the inhibitory effects on both P-gp function and expression. Analogs 2J had less cytotoxicity than other analogs to human PBMCs and RBCs.