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Phytomedicine. 2018 Jul 15;46:184-192. doi: 10.1016/j.phymed.2018.03.037. Epub 2018 Mar 27.

Aqueous extracts of Paeonia suffruticosa modulates mitochondrial proteostasis by reactive oxygen species-induced endoplasmic reticulum stress in pancreatic cancer cells.

Author information

1
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, Taiwan.
2
Graduate Institute of Biomedical Science, Chung Hwa University of Medical Technology, Tainan, Taiwan.
3
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
4
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung, Taiwan; Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, Taiwan.
5
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
6
Department of Life Science, National Taiwan Normal University, No. 88, Ting-Chow Road, Section 4, Taipei, Taiwan; Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: linjy@ntu.edu.tw.

Abstract

BACKGROUND:

Pancreatic cancer (PC) remains the leading cause of cancer mortality, with limited therapeutic targets, and alterations in endoplasmic reticulum (ER)-related proteostasis may be a potential target for therapy. The root bark of Paeonia suffruticosa has been shown to inhibit cancer growth and metastasis, although its impact on PC is unknown.

PURPOSE:

To ascertain the anti-cancer effects of P. suffruticosa on oncogenic functions of PC and determine the detailed molecular mechanisms.

STUDY DESIGN:

Efficacy assessment of extracts, in vitro using PC cells as a model system and in vivo in mouse xenograft tumors.

METHODS:

P. suffruticosa aqueous extracts (PS) were prepared and assessed using liquid chromatography-tandem mass spectrometry. Cell viability, proteins, and cell components were measured using MTT assay, western blotting, and immunofluorescence. Cell apoptosis, cell cycle, and migration were assessed using colorimetric assays, fluorescence activated cell sorting, and transwell migration. Reactive oxygen species (ROS) were evaluated with a commercial 2'-7'-dichlorofluorescin diacetate kit. For the xenograft model, AsPC1 cells were inoculated subcutaneously into immunocompromised mice and PS (oral) was administered over 3 weeks with or without gemcitabine (GEM, intraperitoneal), a first-line advanced/metastatic PC therapy.

RESULTS:

PS stimulated ER stress and affected mitochondrial membrane potential to increase autophagosome numbers and block their degradation, followed by autophagy induction and finally cell apoptosis. Additionally, PS-mediated proteostasis impairment resulted in altered dynamics of the actin cytoskeleton, cell motility impairment, and cell cycle progression inhibition. Conversely, a ROS scavenger partially reversed PS-mediated degradation of peptidyl-prolyl cis-trans isomerase B (PPIB), an ER protein important for protein folding, suggesting that ROS generation by PS may be the upstream of PS-triggering of mitophagy and final cell apoptosis. Nevertheless, oral administration of PS, alone or in combination with GEM, delayed tumor growth in a xenograft model without affecting body weight.

CONCLUSION:

These findings indicate that PS may constitute a potential new alternative or complementary medicine for PC.

KEYWORDS:

Apoptosis; Autophagy; Chinese herbal medicine; Paeonia suffruticosa; Pancreatic cancer; Proteostasis

PMID:
30097117
DOI:
10.1016/j.phymed.2018.03.037
[Indexed for MEDLINE]

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