The synthetic ajoene analog SPA3015 induces apoptotic cell death through crosstalk between NF-κB and PPARγ in multidrug-resistant cancer cells. (October 2016)

• Record Type: Journal Article
• Authors: Hwang, Jee Won; Cho, Hyewon; Lee, Jae Yeon; Jeon, Youngsic; Kim, Su-Nam; Lee, Sang Jin; Bae, Gyu-Un; Yoon, Sungpil; Jeon, Raok; Kim, Yong Kee
• Is Part Of: Food and chemical toxicology. Volume 96(2016)
• Page Start: 35
• Page End: 42
• Publication Date: 2016-10
• Subjects: SPA3015 -- Multidrug resistance -- Apoptosis -- NF-κB -- PPARγ; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2016.07.020
• Languages: English
• ISSNs: 0278-6915

Abstract

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. Highlights: The synthetic ajoene analog SPA3015 has apoptotic potential against MDR cancer cells. The apoptotic potential of SPA3015 is associated with suppression of NF-κB target genes. Its underlying mechanism is due to an increase in the physical interaction of NF-κB with PPARγ. SPA3015 can be used as a potential therapeutic agent to overcome MDR in cancer treatment.