title: Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells.
abstract: Curcumin is a polyphenolic compound which possesses anticancer potential. It has been shown to induce cell death in a variety of cancer cells, however, its effect on CAL27‑cisplatin-resistant human oral cancer cells (CAR cells) has not been elucidated to date. The low water solubility of curcumin which leads to poor bioavailability, however, has been highlighted as a major limiting factor. In this study, we utilized water-soluble PLGA curcumin nanoparticles (Cur-NPs), and investigated the effects of Cur-NPs on CAR cells. The results showed Cur-NPs induced apoptosis in CAR cells but exhibited low cytotoxicity to normal human gingival fibroblasts (HGFs) and normal human oral keratinocytes (OKs). Cur-NPs triggered DNA concentration, fragmentation and subsequent apoptosis. Compared to untreated CAR cells, a more detectable amount of Calcein-AM accumulation was found inside the treated CAR cells. Cur-NPs suppressed the protein and mRNA expression levels of MDR1. Both the activity and the expression levels of caspase-3 and caspase-9 were elevated in the treated CAR cells. The Cur-NP-triggered apoptosis was blocked by specific inhibitors of pan-caspase (z-VAD-fmk), caspase-3 (z-DEVD-fmk), caspase-9 (z-LEHD-fmk) and antioxidant agent (N-acetylcysteine; NAC). Cur-NPs increased reactive oxygen species (ROS) production, upregulated the protein expression levels of cleaved caspase-3/caspase-9, cytochrome c, Apaf-1, AIF, Bax and downregulated the protein levels of Bcl-2. Our results suggest that Cur-NPs triggered the intrinsic apoptotic pathway through regulating the function of multiple drug resistance protein 1 (MDR1) and the production of reactive oxygen species (ROS) in CAR cells. Cur-NPs could be potentially efficacious in the treatment of cisplatin-resistant human oral cancer.
authors.affiliation: Department of Dentistry, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Pei-Ying
authors.initials: PY
authors.lastname: Chang
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Peng
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Lee
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.forename: Shih-Chang
authors.initials: SC
authors.lastname: Tsai
authors.forename: Tzong-Ming
authors.initials: TM
authors.lastname: Shieh
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Ming-Gene
authors.initials: MG
authors.lastname: Tu
authors.forename: Michael Yuanchien
authors.initials: MY
authors.lastname: Chen
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017382:Reactive Oxygen Species; D003474:Curcumin; D002945:Cisplatin