The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells

Abstract

Abstract. The prognosis of advanced pancreatic cancer is poor. Established chemotherapy shows only limited efficacy and significant side effects. We investigated how far a combination of trichostatin A (TSA) and gemcitabine synergizes to inhibit proliferation and promotion of apoptosis of pancreatic adenocarcinoma cells in vitro. The human pancreatic carcinoma cells YAPC, DANG and Panc-89 and primary human foreskin fibroblasts as non-malignant controls were cultured under standardized conditions and incubated with gemcitabine und TSA alone (10 -4 to 10 -8 M) or together (10 -6 to 10 -7 M). After 24-72 h the apoptotic rate was analyzed by flow cytometry (propidium iodide, FACS). DNA-synthesis was assessed using bromodeoxyuridine (BrdU) incorporation. Protein was separated for Western blotting against caspase-3 and -8, p21, bax and bcl-2. The combination of TSA und gemcitabine leads to better pro-apoptotic effects than the employment of single substances. Bcl-2, a mitochondrial protein, which protects against apoptosis, was not expressed. Bax, an apoptosis inducing protein, which destabilizes the mitochondrial membrane potential, was increasingly expressed. Combination of TSA and gemcitabine shows promise for treatment of pancreatic cancer in vivo.

Activation of peroxisome proliferator-activated receptor-γ induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP

“…Caspase-3 is one of the most important executioners which is capable of cleaving many important cellular substrates, and caspase-3 mediated cell death plays an important role in pathogenesis and therapy of a variety of cancers (31,32). Our results found that disruption of Δ"m and activation of caspase-3 was highly correlated with CGZ-induced apoptosis in NB4 cells.…”

Epigenetic Changes and Potential Targets in Pancreatic Cancer

“…Although preclinical data suggests that antagomiRs or miRNA replacement therapy is promising for pancreatic cancer models, clinical use is hampered by unresolved drug delivery and the fact that one miRNA also has several target mRNAs, thus possibly being too unspecifi c [ 184 , 185 ]. Overall, as most of the agents highlighted above are currently in early phases of clinical development, no clear data on effi cacy of epigenetic agents in pancreatic cancer are available, but promising preclinical [ 186 ] and early clinical data warrant further development.…”

Molecular determinants of the antitumor effects of trichostatin A in pancreatic cancer cells

“…/CDKN1A, and regulators of cell survival/death are involved in the mediation of antiproliferative and proapoptotic effects of HDACI [13][14][15]17] . The molecular basis of variations in the biological efficiency of HDACI in different PC cells, however, has not been systematically studied so far.…”

“…With respect to PC, recent experimental studies have suggested that HDACI may efficiently inhibit growth and induce apoptosis even of drug resistant cell lines [13][14][15] . Furthermore, a synergistic action with classic cytostatic drugs, such as gemcitabine, has been demonstrated [16][17][18] . We have recently shown that HDACI also exert antifibrotic efficiency by inhibiting functions of pancreatic stellate cells [19] .…”

“…Waf1 /CDKN1A [14,17] ) and modulation of pro-apoptotic pathways [13,15,17] have been implicated in HDACI action, the molecular determinants of HDACI efficacy or ineffectiveness are currently unclear. Here, we have chosen three human PC cell lines that differ in their biological sensitivity to the HDACI trichostatin A (TSA) for a comparison of TSA effects at the molecular level.…”