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Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages

Lena Welsch, Thilo Welsch, Dmitriy I Dovzhanskiy, Klaus Felix, Nathalia A Giese, Dmitri Krysko UGent and Jens Werner (2012) INTERNATIONAL JOURNAL OF ONCOLOGY. 40(2). p.427-435
abstract
Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate.(4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNF alpha after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
macrophages, phagocytosis, RANDOMIZED CONTROLLED-TRIAL, HUMAN BREAST-CARCINOMA, ADJUVANT CHEMOTHERAPY, P21(WAF1) EXPRESSION, BELINOSTAT PXD101, FOLINIC ACID, PHASE-II, IN-VITRO, CANCER, MECHANISMS, apoptosis, pancreatic cancer, histone deacetylase inhibitors, 4-phenylbutyrate
journal title
INTERNATIONAL JOURNAL OF ONCOLOGY
Int. J. Oncol.
volume
40
issue
2
pages
427 - 435
Web of Science type
Article
Web of Science id
000298824400011
JCR category
ONCOLOGY
JCR impact factor
2.657 (2012)
JCR rank
95/196 (2012)
JCR quartile
2 (2012)
ISSN
1019-6439
DOI
10.3892/ijo.2011.1239
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3030103
handle
http://hdl.handle.net/1854/LU-3030103
date created
2012-10-17 09:05:55
date last changed
2012-10-18 10:12:40
@article{3030103,
  abstract     = {Histone deacetylase inhibitors have been found to have potent anticancer activities, partly induced by tumour cell apoptosis. The clearance of apoptotic tumour cells is an important mechanism of antitumour immune surveillance. The aim of this study was to assess the impact of 4-phenylbutyrate.(4-PB) and its immunological effects on the macrophage clearance of apoptotic pancreatic ductal adenocarcinoma (PDAC) cells. To this end, a co-culture system of human macrophages from donors and PDAC patients, and PDAC cell lines (T3M4, PANC-1 and AsPC-1) was established to study the effect of 4-PB. Apoptosis and phagocytic activity were analysed using flow cytometry, and phagocytosis was confirmed by confocal microscopy. Further, p21 expression was quantified by immunoblot analysis. 4-PB treatment (0-10 mM) resulted in a dose-dependent induction of tumour cell apoptosis in two of the cell lines (T3M4 and PANC-1), but it also induced human macrophage apoptosis. The apoptotic effect of gemcitabine on PDAC cells was further enhanced by 4-PB. Moreover, 4-PB led to a dose-dependent overexpression of the cell cycle regulator p21 in tumour cells. In co-culture, apoptotic PDAC cells were phagocytosed by donor macrophages and phagocytosis was increased through tumour cell exposure to 4-PB and/or gemcitabine, whereas phagocytosis of PANC-1 cells was reduced using macrophages of PDAC patients treated with 4-PB. The 4-PB treatment induced human macrophage expression of the pro-angiogenic IL-8 and simultaneously inhibited inflammatory cytokine release through modulation of IL-10 and TNF alpha after phagocytosis of apoptotic PDAC cells. In conclusion, the 4-PB treatment activated tumour cell death in PDAC cells, resulting in tumour cell phagocytosis by macrophages. The latter were characterized by an anti-inflammatory and pro-angiogenic cytokine response demonstrating adverse, tumour-promoting effects of macrophages on tumour cells. Thus, the potential of 4-PB as an anticancer agent against PDAC cannot be reliably assessed without taking into account the complex tumour microenvironment.},
  author       = {Welsch, Lena and Welsch, Thilo and Dovzhanskiy, Dmitriy I and Felix, Klaus and Giese, Nathalia A and Krysko, Dmitri and Werner, Jens},
  issn         = {1019-6439},
  journal      = {INTERNATIONAL JOURNAL OF ONCOLOGY},
  keyword      = {macrophages,phagocytosis,RANDOMIZED CONTROLLED-TRIAL,HUMAN BREAST-CARCINOMA,ADJUVANT CHEMOTHERAPY,P21(WAF1) EXPRESSION,BELINOSTAT PXD101,FOLINIC ACID,PHASE-II,IN-VITRO,CANCER,MECHANISMS,apoptosis,pancreatic cancer,histone deacetylase inhibitors,4-phenylbutyrate},
  language     = {eng},
  number       = {2},
  pages        = {427--435},
  title        = {Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages},
  url          = {http://dx.doi.org/10.3892/ijo.2011.1239},
  volume       = {40},
  year         = {2012},
}

Chicago
Welsch, Lena, Thilo Welsch, Dmitriy I Dovzhanskiy, Klaus Felix, Nathalia A Giese, Dmitri Krysko, and Jens Werner. 2012. “Impact of the Histone Deacetylase Inhibitor 4-phenylbutyrate on the Clearance of Apoptotic Pancreatic Carcinoma Cells by Human Macrophages.” International Journal of Oncology 40 (2): 427–435.
APA
Welsch, L., Welsch, T., Dovzhanskiy, D. I., Felix, K., Giese, N. A., Krysko, D., & Werner, J. (2012). Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages. INTERNATIONAL JOURNAL OF ONCOLOGY, 40(2), 427–435.
Vancouver
1.
Welsch L, Welsch T, Dovzhanskiy DI, Felix K, Giese NA, Krysko D, et al. Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the clearance of apoptotic pancreatic carcinoma cells by human macrophages. INTERNATIONAL JOURNAL OF ONCOLOGY. 2012;40(2):427–35.
MLA
Welsch, Lena, Thilo Welsch, Dmitriy I Dovzhanskiy, et al. “Impact of the Histone Deacetylase Inhibitor 4-phenylbutyrate on the Clearance of Apoptotic Pancreatic Carcinoma Cells by Human Macrophages.” INTERNATIONAL JOURNAL OF ONCOLOGY 40.2 (2012): 427–435. Print.