Pterostilbene Enhances Cytotoxicity and Chemosensitivity in Human Pancreatic Cancer Cells.

Yi-Hao Hsu,Sheng-Yi Chen,Sheng-Yang Wang,Jer-An Lin,Gow-Chin Yen

doi:10.3390/biom10050709

Yi-Hao Hsu, Sheng-Yi Chen + Show 3 more

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https://doi.org/10.3390/biom10050709

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Journal: Biomolecules	Publication Date: May 4, 2020
Citations: 22	License type: CC BY 4.0

Affiliation: National Chung Hsing University

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.

Highlights

Over 90% of pancreatic ductal adenocarcinomas (PDACs) are exocrine pancreatic cancer, which is a highly malignant tumor that with the growing cause of cancer-related mortality worldwide
Cell cycle analysis with propidium iodide (PI) staining showed that S-phase arrest was induced in PTE-treated MIA PaCa-2 cells compared to untreated cells in a dose-dependent manner (Figure 2A)
Similar results were observed in GEM-resistant cells (Figure 2B), indicating that cell proliferation inhibition was induced via PTE-induced S-phase cell cycle arrest in both cell types

Summary

Introduction

Over 90% of pancreatic ductal adenocarcinomas (PDACs) are exocrine pancreatic cancer, which is a highly malignant tumor that with the growing cause of cancer-related mortality worldwide. In the early stages of PDAC, the signs or symptoms are rarely noticeable, and patients often have local invasion or distant metastasis at diagnosis. Less than 15%–20% of stage I-II PDAC patients are resectable due to most PDAC patients have carcinoma in-situ intravasation, perineural invasion, and distant metastasis at diagnosis [1]. The poor prognosis and outcomes of PDAC patients lead to a low five-year survival rate (6%) and a high incidence [2]. A report by the American Association for Cancer Research (AACR) estimated that PDAC may grow into the second leading cause of cancer-associated deaths by 2030 [3]. PDAC is a silent disease that remains a therapeutic challenge

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