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Pterostilbene Enhances Cytotoxicity and Chemosensitivity in Human Pancreatic Cancer Cells
Yi-Hao Hsu1, Sheng-Yi Chen1, Sheng-Yang Wang2
1Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan.
Abstract:
Gemcitabine (GEM) drug resistance causes high mortality rates and poor outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. Receptor for advanced glycation end products (RAGE) involvement in the GEM resistance process has been demonstrated. Therefore, finding a safe and effective way to inhibit receptors for RAGE-initiated GEM resistance is urgent. Pterostilbene (PTE), a natural methoxylated analogue derived from resveratrol and found in grapes and blueberries, has diverse bioactivities, such as antioxidative, anti-inflammatory, and anticancer qualities. The overall research objective was to determine the potential of PTE to enhance tumor cytotoxicity and chemosensitivity in PDAC cells. Our results have demonstrated that PTE induced S-phase cell cycle arrest, apoptosis, and autophagic cell death and inhibited multidrug resistance protein 1 (MDR1) expression by downregulating RAGE/PI3K/Akt signaling in both MIA PaCa-2 and MIA PaCa-2 GEMR cells (GEM-resistant cells). Remarkably, convincing evidence was established by RAGE small interfering RNA transfection. Taken together, our study demonstrated that PTE promoted chemosensitivity by inhibiting cell proliferation and MDR1 expression via the RAGE/PI3K/Akt axis in PDAC cells. The observations in these experiments indicate that PTE may play a crucial role in MDR1 modulation for PDAC treatment.
Insights
Pterostilbene (PTE) overcomes gemcitabine resistance in pancreatic cancer by inhibiting RAGE signaling, reducing multidrug resistance protein 1 (MDR1) expression, and enhancing chemosensitivity. This natural compound offers a potential new strategy for pancreatic ductal adenocarcinoma (PDAC) treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Gemcitabine (GEM) resistance is a major challenge in pancreatic ductal adenocarcinoma (PDAC) treatment, leading to poor patient outcomes.
- Receptor for advanced glycation end products (RAGE) signaling is implicated in the development of GEM resistance in PDAC.
- There is an urgent need for novel therapeutic strategies to overcome GEM resistance in PDAC.
Purpose of the Study:
- To investigate the potential of pterostilbene (PTE), a natural compound, to enhance chemosensitivity and overcome GEM resistance in PDAC cells.
- To elucidate the molecular mechanisms underlying PTE's effects on GEM-resistant PDAC cells, focusing on RAGE signaling and multidrug resistance protein 1 (MDR1) expression.
Main Methods:
- Utilized MIA PaCa-2 and GEM-resistant MIA PaCa-2 (MIA PaCa-2 GEMR) cell lines to evaluate PTE's effects.
- Assessed PTE's impact on cell cycle progression, apoptosis, and autophagic cell death.
- Investigated the modulation of RAGE/PI3K/Akt signaling pathway and MDR1 expression by PTE.
- Employed RAGE small interfering RNA (siRNA) transfection to confirm the role of RAGE in PTE's mechanism of action.
Main Results:
- Pterostilbene (PTE) induced S-phase cell cycle arrest, apoptosis, and autophagic cell death in both sensitive and resistant PDAC cells.
- PTE significantly inhibited multidrug resistance protein 1 (MDR1) expression.
- PTE's effects were mediated by the downregulation of the RAGE/PI3K/Akt signaling pathway.
- RAGE siRNA transfection validated the crucial role of RAGE in PTE's ability to enhance chemosensitivity and inhibit MDR1 expression.
Conclusions:
- Pterostilbene (PTE) demonstrates significant potential in overcoming gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC).
- PTE enhances chemosensitivity by inhibiting cell proliferation and downregulating MDR1 expression through the RAGE/PI3K/Akt signaling axis.
- PTE represents a promising therapeutic agent for modulating multidrug resistance in PDAC treatment.
