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.
Similar content being viewed by others
References
Batova A, Shao LE, Diccianni MB, Yu AL, Tanaka T, Rephaeli A, Nudelman A, Yu J (2002) The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines. Blood 100:3319–3324
Becouarn Y, Agostini C, Trufflandier N, Boulanger V (2001) Oxaliplatin: available data in non-colorectal gastrointestinal malignancies. Crit Rev Oncol Hematol 40:265–272
Buchsbaum DJ, Bonner JA, Grizzle WE, Stackhouse MA, Carpenter M, Hicklin DJ, Bohlen P, Raisch KP (2002) Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation. Int J Radiat Oncol Biol Phys 54:1180–1193
Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413
Cascallo M, Calbo J, Gelpi JL, Mazo A (2000) Modulation of drug cytotoxicity by reintroduction of wild-type p53 gene (Ad5CMV-p53) in human pancreatic cancer. Cancer Gene Ther 7:545–556
Cassidy J, Misset JL (2002) Oxaliplatin-related side effects: characteristics and management. Semin Oncol 29:11–20
Cecconi D, Scarpa A, Donadelli M, Palmieri M, Hamdan M, Astner H, Righetti PG (2003) Proteomic profiling of pancreatic ductal carcinoma cell lines treated with trichostatin-A. Electrophoresis 24:1871–1878
Donadelli M, Costanzo C, Faggioli L, Scupoli MT, Moore PS, Bassi C, Scarpa A, Palmieri M (2003) Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cells. Mol Carcinog 38:59–69
Giovannetti E, Mey V, Danesi R, Mosca I, Del Tacca M (2004) Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines. Clin Cancer Res 10:2936–2943
Haller DG (2003) New perspectives in the management of pancreas cancer. Semin Oncol 30:3–10
Henderson C, Mizzau M, Paroni G, Maestro R, Schneider C, Brancolini C (2003) Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA). J Biol Chem 278:12579–12589
Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, Thiele HG, Honold G, Pantel K, Riethmuller G et al (1993) p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene 8:289–298
Kawato Y, Aonuma M, Hirota Y, Kuga H, Sato K (1991) Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187–4191
Kelly WK, Richon VM, O’Connor O, Curley T, MacGregor-Curtelli B, Tong W, Klang M, Schwartz L, Richardson S, Rosa E, Drobnjak M, Cordon-Cordo C, Chiao JH, Rifkind R, Marks PA, Scher H (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578–3588
Kornmann M, Butzer U, Blatter J, Beger HG, Link KH (2000) Pre-clinical evaluation of the activity of gemcitabine as a basis for regional chemotherapy of pancreatic and colorectal cancer. Eur J Surg Oncol 26:583–587
Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057
Marshall JL, Rizvi N, Kauh J, Dahut W, Figuera M, Kang MH, Figg WD, Wainer I, Chaissang C, Li MZ, Hawkins MJ (2002) A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2:325–332
Monti P, Marchesi F, Reni M, Mercalli A, Sordi V, Zerbi A, Balzano G, Di Carlo V, Allavena P, Piemonti L (2004) A comprehensive in vitro characterization of pancreatic ductal carcinoma cell line biological behavior and its correlation with the structural and genetic profile. Virchows Arch 445:236–247
Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, Gress T, Bassi C, Kloppel G, Kalthoff H, Ungefroren H, Lohr M, Scarpa A (2001) Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 439:798–802
Moore PS, Barbi S, Donadelli M, Costanzo C, Bassi C, Palmieri M, Scarpa A (2004) Gene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells. Biochim Biophys Acta 1693:167–176
Neoptolemos JP, Cunningham D, Friess H, Bassi C, Stocken DD, Tait DM, Dunn JA, Dervenis C, Lacaine F, Hickey H, Raraty MG, Ghaneh P, Buchler MW (2003) Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol 14:675–692
Nervi C, Borello U, Fazi F, Buffa V, Pelicci PG, Cossu G (2001) Inhibition of histone deacetylase activity by trichostatin A modulates gene expression during mouse embryogenesis without apparent toxicity. Cancer Res 61:1247–1249
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500
Patnaik A, Rowinsky EK, Villalona MA, Hammond LA, Britten CD, Siu LL, Goetz A, Felton SA, Burton S, Valone FH, Eckhardt SG (2002) A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. Clin Cancer Res 8:2142–2148
Raymond E, Faivre S, Woynarowski JM, Chaney SG (1998) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25:4–12
Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, Brooks R, Piekarz RL, Tucker E, Figg WD, Chan KK, Goldspiel B, Fojo AT, Balcerzak SP, Bates SE (2002) Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 8:718–728
Sawa H, Murakami H, Ohshima Y, Sugino T, Nakajyo T, Kisanuki T, Tamura Y, Satone A, Ide W, Hashimoto I, Kamada H (2001) Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad. Brain Tumor Pathol 18:109–114
Shi X, Liu S, Kleeff J, Friess H, Buchler MW (2002) Acquired resistance of pancreatic cancer cells towards 5-Fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology 62:354–362
Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I, Coombes RC (2001) Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clin Cancer Res 7:971–976
Yamanaka Y (1992) The immunohistochemical expressions of epidermal growth factors, epidermal growth factor receptors and c-erbB-2 oncoprotein in human pancreatic cancer. Nippon Ika Daigaku Zasshi 59:51–61
Acknowledgements
We thank Dr. E. Pinton and Dr. A. Sbarufatti (Aventis and Sanofi-Synthelabo) for providing irinotecan and oxaliplatin. This study was supported by Fondazione Cassa di Risparmio di Verona (Bando 2004); Fondazione Giorgio Zanotto, Verona, Italy; Associazione Italiana Ricerca sul Cancro, Milan, Italy; and the Italian Ministry of University and Research. Authors Paolo Piacentini and Massimo Donadelli have equally contributed to this paper.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Piacentini, P., Donadelli, M., Costanzo, C. et al. Trichostatin A enhances the response of chemotherapeutic agents in inhibiting pancreatic cancer cell proliferation. Virchows Arch 448, 797–804 (2006). https://doi.org/10.1007/s00428-006-0173-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-006-0173-x