title: Chemosensitizing effects of synthetic curcumin analogs on human multi-drug resistance leukemic cells.
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 by 1J (up to 6-, 11- and 22- folds, respectively) and 2J (up to 7-, 12- and 17- folds, respectively). Besides 2A, 2F and 2J dramatically decreased P-gp expression in K562/Adr cells. These results could be summarized in the following way. Analog 1J inhibited only P-gp function, while 2A and 2F inhibited only P-gp expression. Interestingly, 2J exerts inhibition of both P-gp function and expression. The combination index (CI) of combination between 2J 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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand.
authors.forename: Sariya
authors.initials: S
authors.lastname: Mapoung
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand.
authors.forename: Pornsiri
authors.initials: P
authors.lastname: Pitchakarn
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Yodkeeree
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand; Drug Delivery System Excellence Center, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand.
authors.forename: Chitchamai
authors.initials: C
authors.lastname: Ovatlarnporn
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand; Drug Delivery System Excellence Center, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand.
authors.forename: Natee
authors.initials: N
authors.lastname: Sakorn
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200 Thailand. Electronic address: pornngarm.d@cmu.ac.th.
authors.forename: Pornngarm
authors.initials: P
authors.lastname: Limtrakul
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003474:Curcumin
keywords: Curcumin analogs; Leukemia; Multi-drug resistance; P-gp inhibitor