Ursolic acid promotes apoptosis, autophagy, and chemosensitivity in gemcitabine‐resistant human pancreatic cancer cells

Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural...

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Bibliographic Details
Published in:Phytotherapy research 2020-08, Vol.34 (8), p.2053-2066
Main Authors: Lin, Ji‐Hua, Chen, Sheng‐Yi, Lu, Chi‐Cheng, Lin, Jer‐An, Yen, Gow‐Chin
Format: Article
Language:English
Subjects:
Adenocarcinoma
Advanced glycosylation end products
Antineoplastic Agents, Phytogenic - pharmacology
Antineoplastic Agents, Phytogenic - therapeutic use
Apoptosis
Autophagy
Cell culture
Cell cycle
Cell death
Cell Line, Tumor
Cell Proliferation
Cell viability
Cytotoxicity
Endoplasmic reticulum
Gemcitabine
gemcitabine resistance
Glycosylation
Humans
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - mortality
Phagocytosis
Product safety
RAGE
Survival Rate
Toxicity
Triterpenes - pharmacology
Triterpenes - therapeutic use
Ursolic Acid
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Summary:Gemcitabine (GEM) resistance in pancreatic adenocarcinoma mediated by the receptor for advanced glycation end products (RAGE) has been demonstrated. Therefore, investigating the safety and the potential of new auxiliary methods for pancreatic cancer treatment is urgent. Ursolic acid (UA), a natural pentacyclic triterpenoid found in apple peels, rosemary, and thyme, has been reported to have anticancer capacity. This study aimed to reveal the underlying mechanisms of UA in cell death and drug enhancement, especially in GEM‐resistant pancreatic cancer cells. First, GEM‐resistant cells (MIA Paca‐2GEMR cells) were established by incrementally increasing GEM culture concentrations. UA treatment reduced cell viability through cell cycle arrest and endoplasmic reticulum (ER) stress, resulting in apoptosis and autophagy in a dose‐dependent manner in MIA Paca‐2 and MIA Paca‐2GEMR cells. High RAGE expression in MIA Paca‐2GEMR cells was suppressed by UA treatment. Interestingly, knocking down RAGE expression showed similar UA‐induced effects in both cell lines. Remarkably, UA had a drug‐enhancing effect by decreasing cell viability and increasing cell cytotoxicity when combined with GEM treatment. In conclusions, UA triggered ER stress, subsequently regulating apoptosis‐ and autophagy‐related pathways and increasing GEM chemosensitivity in pancreatic cancer cells by inhibiting the expression of RAGE.
ISSN:0951-418X
1099-1573
DOI:10.1002/ptr.6669