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Open Access Research article

Paraptosis and NF-κB activation are associated with protopanaxadiol-induced cancer chemoprevention

Chong-Zhi Wang12, Binghui Li3, Xiao-Dong Wen12, Zhiyu Zhang12, Chunhao Yu12, Tyler D Calway12, Tong-Chuan He4, Wei Du3 and Chun-Su Yuan1256*

Author Affiliations

1 Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL, USA

2 Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA

3 Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA

4 Department of Surgery, University of Chicago, Chicago, IL, USA

5 Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA

6 Tang Center for Herbal Medicine Research, and Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL, 60637, USA

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BMC Complementary and Alternative Medicine 2013, 13:2  doi:10.1186/1472-6882-13-2

Published: 3 January 2013

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.

Keywords:
Ginseng; Protopanaxadiol; PPD; Paraptosis; Cytoplasmic vacuoles; Mitochondrial swelling; Antioxidant; Cancer chemoprevention