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Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress

ABSTRACT: Background: Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos. In this paper, we investigated the anticancer effects of PA on human chemotherapy resistant pancreatic cancer cells. Methods: Gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2 were used, along with a xenograft model of MIA PaCa-2 cells implanted in mice. Apoptosis was assessed by quantitation of cytoplasmic histone-associated DNA fragments and expression of cleaved PARP. Differential expression of genes was identified using comparative DNA microarray analysis. Protein levels were determined by immunoblotting. Toxicology studies in vivo were assessed by detecting pathological changes in organs and liver enzyme profiles in plasma. Tumor tissues were analyzed by quantification of apoptotic bodies, qRT-PCR and immunoblotting. Principal Findings: PA induced endoplasmic reticulum (ER) stress in chemotherapy resistant pancreatic cancer cells through activation of heat shock response and unfolded protein response related genes, which further triggered apoptosis. The involvement of ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, 25 mg kg−1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis, ER stress related genes and proteins expression. Conclusions: Growth inhibition and induction of apoptosis by PA in chemotherapy resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. Pancreatic cancer cell line treated with pachymic acid vs. control (untreated)

ORGANISM(S): Homo sapiens  

SUBMITTER: shujie cheng   Jeanette N McClintick  Daniel Sliva  Shujie Cheng 

PROVIDER: E-GEOD-64111 | ArrayExpress | 2014-12-12



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