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01-02-2011 | Original Article

Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells

Authors: Cao Yang, Edwin Choy, Francis J. Hornicek, Kirkham B. Wood, Joseph H. Schwab, Xianzhe Liu, Henry Mankin, Zhenfeng Duan

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2011

Abstract

Purpose

To better understand the mechanisms of cytotoxicity and cell death induced by HDACI PCI-24781 in bone sarcoma cells.

Methods

Four bone sarcoma cell lines were treated with PCI-24781, and the cytotoxicity was investigated. Further, accumulation of acetylated histones, p21, and PARP cleavage were evaluated in PCI-24781-treated cells. The synergistic effect of PCI-24781 to doxorubicin and its mechanism was investigated in bone sarcoma cells.

Results

MTT assay demonstrated that the growth of bone sarcoma cells was inhibited after treatment with PCI-24781. Accumulation of acetylated histones, p21, and PARP cleavage were found in PCI-24781-treated cells. Expression of DNA repair protein RAD51 was inhibited, and the expression of apoptosis protein GADD45α was induced by PCI-24781 in bone sarcoma cells. Bone sarcoma cells treated with PCI-24781 become more sensitive to doxorubicin. The caspase-3/7 activity was increased with doxorubicin and PCI-24781 treatment in these cells.

Conclusions

HDACI PCI-24781 has a synergistic effect on doxorubicin-induced apoptosis in bone sarcoma cells.

Adimoolam S, Sirisawad M, Chen J, Thiemann P, Ford JM, Buggy JJ (2007) HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci USA 104:19482–19487CrossRefPubMed

Arnold NB, Arkus N, Gunn J, Korc M (2007) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances gemcitabine-induced cell death in pancreatic cancer. Clin Cancer Res 13:18–26CrossRefPubMed

Banuelos CA, Banath JP, MacPhail SH, Zhao J, Reitsema T, Olive PL (2007) Radiosensitization by the histone deacetylase inhibitor PCI-24781. Clin Cancer Res 13:6816–6826CrossRefPubMed

Baumann P, Benson FE, West SC (1996) Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell 87:757–766CrossRefPubMed

Benson FE, Stasiak A, West SC (1994) Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO J 13:5764–5771PubMed

Buggy JJ, Cao ZA, Bass KE, Verner E, Balasubramanian S, Liu L, Schultz BE, Young PR, Dalrymple SA (2006) CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther 5:1309–1317CrossRefPubMed

Carew JS, Giles FJ, Nawrocki ST (2008) Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett 269:7–17CrossRefPubMed

Dowdy SC, Jiang S, Zhou XC, Hou X, Jin F, Podratz KC, Jiang SW (2006) Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Mol Cancer Ther 5:2767–2776CrossRefPubMed

Drummond DC, Noble CO, Kirpotin DB, Guo Z, Scott GK, Benz CC (2005) Clinical development of histone deacetylase inhibitors as anticancer agents. Annu Rev Pharmacol Toxicol 45:495–528CrossRefPubMed

10.

Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K (2003) Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2:971–984PubMed

11.

Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23CrossRefPubMed

12.

Gupta RC, Bazemore LR, Golub EI, Radding CM (1997) Activities of human recombination protein Rad51. Proc Natl Acad Sci USA 94:463–468CrossRefPubMed

13.

Helman LJ, Meltzer P (2003) Mechanisms of sarcoma development. Nat Rev Cancer 3:685–694CrossRefPubMed

14.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96CrossRefPubMed

15.

Jiang T, Soprano DR, Soprano KJ (2007) GADD45A is a mediator of CD437 induced apoptosis in ovarian carcinoma cells. J Cell Physiol 212:771–779CrossRefPubMed

16.

Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291–7300PubMed

17.

Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G, Zhu QS, Bornmann WG, McConkey DJ, Pollock RE, Lev DC (2009) Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res 15:3472–3483CrossRefPubMed

18.

Lourda M, Trougakos IP, Gonos ES (2007) Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of Clusterin/Apolipoprotein J. Int J Cancer 120:611–622CrossRefPubMed

19.

Maiso P, Colado E, Ocio EM, Garayoa M, Martin J, Atadja P, Pandiella A, San-Miguel JF (2009) The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 23(12):2265–2274

20.

Manara MC, Perdichizzi S, Serra M, Pierini R, Benini S, Hattinger CM, Astolfi A, Bagnati R, D’Incalci M, Picci P, Scotlandi K (2005) The molecular mechanisms responsible for resistance to ET-743 (Trabectidin; Yondelis) in the Ewing’s sarcoma cell line, TC-71. Int J Oncol 27:1605–1616PubMed

21.

Mohrenweiser HW, Wilson DM 3rd, Jones IM (2003) Challenges and complexities in estimating both the functional impact and the disease risk associated with the extensive genetic variation in human DNA repair genes. Mutat Res 526:93–125PubMed

22.

Mullan PB, Quinn JE, Gilmore PM, McWilliams S, Andrews H, Gervin C, McCabe N, McKenna S, White P, Song YH, Maheswaran S, Liu E, Haber DA, Johnston PG, Harkin DP (2001) BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. Oncogene 20:6123–6131CrossRefPubMed

23.

Nawrocki ST, Carew JS, Douglas L, Cleveland JL, Humphreys R, Houghton JA (2007) Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. Cancer Res 67:6987–6994CrossRefPubMed

24.

Patel SR, Vadhan-Raj S, Papadopolous N, Plager C, Burgess MA, Hays C, Benjamin RS (1997) High-dose ifosfamide in bone and soft tissue sarcomas: results of phase II and pilot studies–dose-response and schedule dependence. J Clin Oncol 15:2378–2384PubMed

25.

Picci P, Bacci G, Ferrari S, Mercuri M (1997) Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8:1107–1115CrossRefPubMed

26.

Richardson C (2005) RAD51, genomic stability, and tumorigenesis. Cancer Lett 218:127–139CrossRefPubMed

27.

Rikiishi H, Shinohara F, Sato T, Sato Y, Suzuki M, Echigo S (2007) Chemosensitization of oral squamous cell carcinoma cells to cisplatin by histone deacetylase inhibitor, suberoylanilide hydroxamic acid. Int J Oncol 30:1181–1188PubMed

28.

Ruefli AA, Ausserlechner MJ, Bernhard D, Sutton VR, Tainton KM, Kofler R, Smyth MJ, Johnstone RW (2001) The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci USA 98:10833–10838CrossRefPubMed

29.

Shahbazian MD, Grunstein M (2007) Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 76:75–100CrossRefPubMed

30.

Shao L, Kasanov J, Hornicek FJ, Morii T, Fondren G, Weissbach L (2003) Ecteinascidin-743 drug resistance in sarcoma cells: transcriptional and cellular alterations. Biochem Pharmacol 66:2381–2395CrossRefPubMed

31.

Smith KT, Workman JL (2009) Histone deacetylase inhibitors: anticancer compounds. Int J Biochem Cell Biol 41:21–25CrossRefPubMed

32.

Steinert DM, Blakely LJ, Salganick J, Trent JC (2003) Molecular targets in therapy for human soft-tissue and bone sarcomas. Curr Oncol Rep 5:295–303CrossRefPubMed

33.

Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64:435–459CrossRefPubMed

34.

Tavera-Mendoza LE, Quach TD, Dabbas B, Hudon J, Liao X, Palijan A, Gleason JL, White JH (2008) Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist. Proc Natl Acad Sci USA 105:8250–8255CrossRefPubMed

35.

Walkinshaw DR, Yang XJ (2008) Histone deacetylase inhibitors as novel anticancer therapeutics. Curr Oncol 15:237–243PubMed

36.

Yang C, Yang S, Wood KB, Hornicek FJ, Schwab JH, Fondren G, Mankin H, Duan Z (2009) Multidrug resistant osteosarcoma cell lines exhibit deficiency of GADD45alpha expression. Apoptosis 14:124–133CrossRefPubMed

37.

Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q (2005) Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci USA 102:16090–16095CrossRefPubMed

Title: Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells
Authors: Cao Yang
Edwin Choy
Francis J. Hornicek
Kirkham B. Wood
Joseph H. Schwab
Xianzhe Liu
Henry Mankin
Zhenfeng Duan
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1344-7

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