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

• Published in: Phytotherapy research Vol. 34; no. 8; pp. 2053 - 2066
• Main Authors: Lin, Ji‐Hua, Chen, Sheng‐Yi, Lu, Chi‐Cheng, Lin, Jer‐An, Yen, Gow‐Chin
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2020; Wiley Subscription Services, Inc
• Subjects: Adenocarcinoma; advanced glycation end products; Advanced glycosylation end products; Antifungal agents; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis; apple peels; Autophagy; Cell culture; Cell cycle; cell cycle checkpoints; Cell death; Cell Line, Tumor; cell lines; Cell Proliferation; Cell viability; Cytotoxicity; dose response; drugs; Endoplasmic reticulum; Gemcitabine; gemcitabine resistance; Glycosylation; Humans; methodology; neoplasm cells; Pancreatic cancer; pancreatic neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - mortality; Phagocytosis; phytotherapy; Product safety; RAGE; rosemary; Survival Rate; thyme; Toxicity; Triterpenes - pharmacology; Triterpenes - therapeutic use; Ursolic Acid; apoptosis; pancreatic cancer; autophagy; RAGE; gemcitabine resistance; ursolic acid
• ISSN: 0951-418X; 1099-1573; 1099-1573
• DOI: 10.1002/ptr.6669

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.