Abstract
Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Activating Transcription Factor 4 / genetics
-
Activating Transcription Factor 4 / metabolism
-
Animals
-
Antineoplastic Agents / isolation & purification
-
Antineoplastic Agents / pharmacology*
-
Apoptosis / drug effects
-
Cell Line, Tumor
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Deoxycytidine / analogs & derivatives
-
Deoxycytidine / pharmacology
-
Drug Resistance, Neoplasm / drug effects
-
Endoplasmic Reticulum Stress / drug effects*
-
Eukaryotic Initiation Factor-2 / genetics
-
Eukaryotic Initiation Factor-2 / metabolism
-
Female
-
Gemcitabine
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic*
-
HSP70 Heat-Shock Proteins / genetics
-
HSP70 Heat-Shock Proteins / metabolism
-
Humans
-
Mice
-
Mice, Nude
-
Pancreas / drug effects*
-
Pancreas / metabolism
-
Pancreas / pathology
-
Pancreatic Neoplasms / drug therapy*
-
Pancreatic Neoplasms / genetics
-
Pancreatic Neoplasms / metabolism
-
Pancreatic Neoplasms / pathology
-
Poria / chemistry*
-
Regulatory Factor X Transcription Factors
-
Signal Transduction
-
Taurochenodeoxycholic Acid / pharmacology
-
Transcription Factor CHOP / genetics
-
Transcription Factor CHOP / metabolism
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Triterpenes / isolation & purification
-
Triterpenes / pharmacology*
-
Unfolded Protein Response / drug effects
-
X-Box Binding Protein 1
-
Xenograft Model Antitumor Assays
Substances
-
ATF4 protein, human
-
Antineoplastic Agents
-
DDIT3 protein, human
-
DNA-Binding Proteins
-
Eukaryotic Initiation Factor-2
-
HSP70 Heat-Shock Proteins
-
Regulatory Factor X Transcription Factors
-
Transcription Factors
-
Triterpenes
-
X-Box Binding Protein 1
-
XBP1 protein, human
-
Xbp1 protein, mouse
-
Deoxycytidine
-
Activating Transcription Factor 4
-
Transcription Factor CHOP
-
Taurochenodeoxycholic Acid
-
ursodoxicoltaurine
-
pachymic acid
-
Gemcitabine
Grants and funding
This study was supported by research grants from China Scholarship Council and EcoNugenics, Inc., Santa Rosa, CA, USA. The Center for Medical Genomics is supported in part by the Indiana Genomics Initiative at Indiana University (INGEN, which is supported in part by the Lilly Endowment, Inc.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funder, Econugenics, Inc., provided support in the form of salary for Dr. Isaac Eliaz, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.