Chloroquine potentiates the anticancer effect of pterostilbene on pancreatic cancer by inhibiting autophagy and downregulating the rage/stat3 pathway
Journal
Molecules
Journal Volume
26
Journal Issue
21
Date Issued
2021
Author(s)
Abstract
The treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, because pro-survival signaling pathways—such as the receptor for advanced glycation end products (RAGE)/signal transducer and activator of transcription 3 (STAT3) pathway—are overexpressed in PDAC cells. Moreover, PDAC cells are highly resistant to chemotherapeutic agents because of autophagy induction. Therefore, autophagy and its modulated signaling pathways are attractive targets for developing novel therapeutic strategies for PDAC. Pterostilbene is a stilbenoid chemically related to resveratrol, and has potential for the treatment of cancers. Accordingly, we investigated whether the autophagy inhibitor chloroquine could potentiate the anticancer effect of pterostilbene in the PDAC cell lines MIA PaCa-2 and BxPC-3, as well as in an orthotopic animal model. The results indicated that pterostilbene combined with chloroquine significantly inhibited autophagy, decreased cell viability, and sensitized the cells to pterostilbene-induced apoptosis via downregulation of the RAGE/STAT3 and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways in PDAC cells. The results of the orthotopic animal model showed that pterostilbene combined with chloroquine significantly inhibited pancreatic cancer growth, delayed tumor quadrupling times, and inhibited autophagy and STAT3 in pancreatic tumors. In summary, the present study suggested the novel therapeutic strategy of pterostilbene combined with chloroquine against the growth of pancreatic ductal adenocarcinoma by inhibiting autophagy and downregulating the RAGE/STAT3 signaling pathways. ? 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
Apoptosis
Autophagy
Chloroquine
Pancreatic ductal adenocarcinoma
Pterostilbene
RAGE/STAT3
antineoplastic agent
chloroquine
mitogen activated protein kinase
MOK protein, human
pterostilbene
STAT3 protein
STAT3 protein, human
stilbene derivative
tumor antigen
autophagy
cell culture
cell proliferation
cell survival
chemistry
down regulation
drug effect
drug screening
human
metabolism
pancreas carcinoma
pancreas tumor
pathology
Antigens, Neoplasm
Antineoplastic Agents
Carcinoma, Pancreatic Ductal
Cell Proliferation
Cell Survival
Cells, Cultured
Down-Regulation
Drug Screening Assays, Antitumor
Humans
Mitogen-Activated Protein Kinases
Pancreatic Neoplasms
STAT3 Transcription Factor
Stilbenes
SDGs
Type
journal article