title: The synthetic ajoene analog SPA3015 induces apoptotic cell death through crosstalk between NF-κB and PPARγ in multidrug-resistant cancer cells.
abstract: Multidrug resistance (MDR) caused by P-glycoprotein (P-gp) overexpression impedes successful cancer chemotherapy. In this study, we investigated the anticancer effects of SPA3015, a synthetic ajoene analog, in P-gp-overexpressing MDR cancer cells (KBV20C and MES-SA/DX5). Treatment with SPA3015 caused a dramatic decrease in the cell viabilities of both KBV20C and MES-SA/DX5 cells. This decrease was accompanied by apoptotic cell death without affecting the expression level or drug efflux function of P-gp. SPA3015 selectively suppressed NF-κB reporter gene activity, which led to decreased expression of NF-κB target genes such as CIAP1, CIAP2, XIAP, and Bcl-XL. Surprisingly, nuclear localization and DNA binding affinity of the p65 subunit were not affected by SPA3015, suggesting that SPA3015 inhibits the transcriptional activity of NF-κB at the nucleus. Indeed, SPA3015 treatment led to an increase in the physical interaction of p65 with PPARγ, which resulted in the inhibition of NF-κB activity. Our findings support the hypothesis that SPA3015 inhibits NF-κB transcriptional activity by facilitating the physical interaction of the p65 subunit and PPARγ, which leads to apoptotic cell death in MDR cancer cells.
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Jee Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Cho
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea; Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute, Gangneung, Gangwon-do 25451, Republic of Korea.
authors.forename: Youngsic
authors.initials: Y
authors.lastname: Jeon
authors.affiliation: Natural Products Research Center, Korea Institute of Science and Technology Gangneung Institute, Gangneung, Gangwon-do 25451, Republic of Korea.
authors.forename: Su-Nam
authors.initials: SN
authors.lastname: Kim
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Gyu-Un
authors.initials: GU
authors.lastname: Bae
authors.affiliation: Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do 10408, Republic of Korea.
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea. Electronic address: yksnbk@sookmyung.ac.kr.
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D016328:NF-kappa B; D047495:PPAR gamma; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C000615644:SPA3015; D013454:Sulfoxides; C048980:ajoene
keywords: Apoptosis; Multidrug resistance; NF-κB; PPARγ; SPA3015