Impact of the histone deacetylase inhibitor 4-phenylbutyrate on the             clearance of apoptotic pancreatic carcinoma cells by human macrophages.
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 TNFα 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.
Department of General, Visceral and Transplantation Surgery,                     University of Heidelberg, Heidelberg, Germany.
Lena
L
Welsch
Thilo
T
Welsch
Dmitriy I
DI
Dovzhanskiy
Klaus
K
Felix
Nathalia A
NA
Giese
Dmitri V
DV
Krysko
Jens
J
Werner
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010587:Phagocytosis / Q000187:drug effects*; D010654:Phenylbutyrates / Q000494:pharmacology*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; D003841:Deoxycytidine; C075773:4-phenylbutyric acid; D000093542:Gemcitabine