Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation

Abstract

Pancreatic cancer is an aggressive neoplasia, and standard chemotherapies are by and large ineffective. The purpose of this work was to get a comprehensive preclinical study on the ability of anticancer drug combinations that best inhibit growth of pancreatic adenocarcinoma cells. We evaluated the in vitro growth inhibition of ten pancreatic cancer cell lines to gemcitabine and 5-fluorouracil, newer generation cytotoxic agents (oxaliplatin, irinotecan), targeted therapy (gefitinib) and a histone deacetylase (HDAC) inhibitor (trichostatin A). Cells were treated with the single drug alone and all pairwise drug association. Our results demonstrate that TSA can effectively increase the drug sensitivity of all the cell lines studied. The association of TSA and irinotecan determines an increase in growth inhibition on the highest percentage of cell lines (80%). Our findings may represent an experimental basis for potential clinical application of HDAC inhibitors, in particular in association with drugs used in cancer clinical treatment, supporting the idea that HDAC inhibitors could act as sensitizers for chemotherapy.

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

“…1). These effects confirm the results of Piacentini et al (10). The main effect of inducing cell apoptosis must be the efficacy of TSA, because TSA as single agent leads to a higher rate of apoptosis than gemcitabine as single agent in equal concentrations, e.g.…”

“…Besides affecting the expression of proteins regulating progression of the cell cycle, TSA modulates regulators of apoptosis, such as caspases (7). Until now the effect of HDACi combinated with chemo-therapy on pancreatic carcinoma cells has been explored in a few experiments only, without investigating possible signal transduction pathways (10). However, the combination of HDACi and chemotherapeutic agents was successful in hepatoma cells (11).…”

Effects of the HDAC inhibitor CG2 in combination with irinotecan, 5-fluorouracil, or oxaliplatin on HCT116 colon cancer cells and xenografts

“…A combined effect of TSA and irinotecan, acting on pancreatic and gastric cancer cells, has also been reported (12,13). We previously demonstrated that PXD101 in combination with irinotecan dramatically enhanced the anti-tumor effect of each agent alone in in vitro and in vivo models of colon cancer (10).…”

Synergistic antitumor effect between vorinostat and topotecan in small cell lung cancer cells is mediated by generation of reactive oxygen species and DNA damage-induced apoptosis

“…Our results are confirmed by the synergism observed in a panel of ovarian cancer cells or pancreatic cancer cells treated simultaneously with a HDACI (even in low doses; refs. 15,43) and the topo-I inhibitors topotecan or CPT11 (irinotecan hydrochloride hydrate), respectively. On the other hand, in contrast to our data, Kim et al reported in one glioblastoma cell line that the HDACI trichostatin A given before or simultaneously did not potentiate camptothecin-induced cell killing (41).…”