Inhibition of Autophagy Strengthens Celastrol-Induced Apoptosis in Human Pancreatic Cancer In Vitro and In Vivo Models

ISSN: 1875-5666 (Online)
ISSN: 1566-5240 (Print)


Volume 14, 10 Issues, 2014


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Current Molecular Medicine

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David W. Li
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University of Nebraska Medical Center
Omaha, NE
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Inhibition of Autophagy Strengthens Celastrol-Induced Apoptosis in Human Pancreatic Cancer In Vitro and In Vivo Models

Author(s): X. Zhao, S. Gao, H. Ren, H. Huang, W. Ji and J. Hao

Affiliation: Department of Pancreatic Carcinoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

Abstract

Objectives: Celastrol, a quinone methide triterpenoid, could induce apoptosis in pancreatic cancer cells. The purpose of this study is to determine whether there is protective autophagy after celastrol treatment in pancreatic cancer cells and the synergistic effects of celastrol and 3-MA in vitro and in vivo.

Methods: The cells viability was measured using MTT assays. Degree of apoptosis and amount of autophagic vacuoles were measured by flow cytometry. Immunofluorescence was adapted to monitor the localization of autophagic protein LC3-II. Expression of LC3-II, cleaved caspase-3, Bax and bcl-2 was detected by immunoblot. Autophagosomes were observed by electron microscopy. The synergistic effect of celastrol and 3- MA in vivo was studied in the MiaPaCa-2 xenograft tumor model.

Results: Celastrol increased the level of autophagy in pancreatic cancer cells. Furthermore in vitro, when inhibiting the autophagy with 3-MA, the level of celastrol-induced apoptosis elevated; after upgrading autophagy by starvation, the level of celastrol-induced apoptosis descended. 3-MA enhanced celastrol-induced apoptosis and inhibitory effect on tumor growth in vivo.

Conclusions: In pancreatic cancer, celastrol treatment increased the level of autophagy to protect cancer cells against apoptosis. Autophagy inhibitor 3-MA could improve the therapeutic effect of celastrol in vitro and in vivo.


Keywords: 3-methyladenine, apoptosis, autophagy, celastrol, pancreatic cancer, PTEN.

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Article Details

Volume: 14
Issue Number: 4
First Page: 555
Last Page: 563
Page Count: 9
DOI: 10.2174/1566524014666140414211223
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