Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer

Abstract

BackgroundTreatment options for pancreatic ductal adenocarcinoma (PDAC) are limited. Histone deacetylase inhibitors are a new and promising drug family with strong anticancer activity. The aim of this study was to examine the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitor belinostat on the growth of human PDAC cells.MethodsThe proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1) was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21Cip1/Waf1 and acetylated histone H4 (acH4) expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67.ResultsTreatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation.ConclusionExperimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting.

Chemoradiotherapy screening in a novel biomimetic polymer based pancreatic cancer model

“…It should be stated that all reported in vitro studies have a different time-regime, i.e., our long-term study is more aligned with the time-frame of animal experiments 2,11,14,17,23,55,78,79,95 ( Fig. 7) and clinical trials, 56,58,69,73,105,106 pointing to the great potential of our scaffold in providing a reproducible, low cost powerful tool for replacing animals in long-term realistic treatment screening for PDAC.…”

“…6 More specically, the socalled tumour microenvironment (TME), which is a cocktail of biochemical, cellular, biomechanical and structural components has been shown to affect the efficiency of treatment delivery to the tumour. 4,[7][8][9] Traditionally, PDAC research including treatment screening, is conducted in (a) 2D in vitro systems [10][11][12][13] (tissue culture asks or Petri-plates) or in (b) animals, mainly mice. 10,11,[14][15][16][17][18] Generally, 2D in vitro cultures are responsive to radiotherapy and chemotherapy, reproducible and very easy to use.…”

“…4,[7][8][9] Traditionally, PDAC research including treatment screening, is conducted in (a) 2D in vitro systems [10][11][12][13] (tissue culture asks or Petri-plates) or in (b) animals, mainly mice. 10,11,[14][15][16][17][18] Generally, 2D in vitro cultures are responsive to radiotherapy and chemotherapy, reproducible and very easy to use. 4,13,19 However, the system is unable to capture key features of the TME such as structure, stiffness, spatial orientation, cell-cell cross talk, cellextracellular matrix (ECM) interactions and environmental gradients.…”

“…More specically, as described above, most treatment studies in spheroids have been monitored for a maximum of 7 days, 32,34,35,52 which is signicantly shorter in comparison to patients' treatment time-frame and to animal models which are usually assessed over a time frame of several weeks. 2,11,[14][15][16][17][55][56][57] Furthermore, in vitro models that allow long term post-treatment monitoring would enable the conduction of fractionated radiation screening wherein radiotherapeutic treatment is provided to the patients in serial smaller dosages over a specic time interval to minimise radiation related side effects. [58][59][60][61] We have recently developed a robust polyurethane (PU) scaffold for PDAC (re-)modelling, which overcomes some of the challenges faced in spheroid systems.…”

Epigenetic targeting in pancreatic cancer

“…The results showed synergistic antiproliferative and proapoptotic effects of the two drugs in pancreatic cancer cell lines [72]. More recently, two studies showed that belinostat induces growth inhibition, in vitro and in vivo in immunodeficient mice, alone or synergistically with gemcitabine [73,74].…”