title: Paraptosis and NF-κB activation are associated with protopanaxadiol-induced cancer chemoprevention.
abstract: BACKGROUND
  Protopanaxadiol (PPD) is a triterpenoid that can be prepared from steamed ginseng. PPD possesses anticancer potential via caspase-dependent apoptosis. Whether paraptosis, a type of the caspase-independent cell death, is also induced by PPD has not been evaluated.
  
  
  METHODS
  Cell death, the cell cycle and intracellular reactive oxygen species (ROS) were analyzed by flow cytometry after staining with annexin V/PI, PI/RNase or H2DCFDA. We observed morphological changes by crystal violet staining assay. Mitochondrial swelling was measured by ultraviolet-visible spectrophotometry. The activation of NF-κB was measured by luciferase reporter assay.
  
  
  RESULTS
  At comparable concentrations of 5-fluorouracil, PPD induced more cell death in human colorectal cancer cell lines HCT-116 and SW-480. We demonstrated that PPD induced paraptosis in these cancer cells. PPD treatment significantly increased the percentage of cancer cells with cytoplasmic vacuoles. After the cells were treated with PPD and cycloheximides, cytoplasmic vacuole generation was inhibited. The paraptotic induction effect of PPD was also supported by the results of the mitochondrial swelling assay. PPD induced ROS production in cancer cells, which activated the NF-κB pathway. Blockage of ROS by NAC or PS-1145 inhibited the activation of NF-κB signaling.
  
  
  CONCLUSIONS
  PPD induces colorectal cancer cell death in part by induction of paraptosis. The anticancer activity of PPD may be enhanced by antioxidants such as green tea, which also inhibit the activation of NF-κB signaling.
authors.affiliation: Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL, USA.
authors.forename: Chong-Zhi
authors.initials: CZ
authors.lastname: Wang
authors.forename: Binghui
authors.initials: B
authors.lastname: Li
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wen
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chunhao
authors.initials: C
authors.lastname: Yu
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Calway
authors.forename: Tong-Chuan
authors.initials: TC
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Chun-Su
authors.initials: CS
authors.lastname: Yuan
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D005894:Panax / Q000737:chemistry*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012502:Sapogenins / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D014617:Vacuoles / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D010936:Plant Extracts; D011725:Pyridines; D017382:Reactive Oxygen Species; D012502:Sapogenins; C062916:protopanaxadiol