Antitumour effect of valproic acid against salivary gland cancer in vitro and in vivo

Nagai,Hirokazu; Fujioka-Kobayashi,Masako; Ohe,Go; Hara,Kanae; Takamaru,Natsumi; Uchida,Daisuke; Tamatani,Tetsuya; Fujisawa,Kenji; Miyamoto,Youji

doi:10.3892/or.2013.2959

Antitumour effect of valproic acid against salivary gland cancer in vitro and in vivo

Authors:
- Hirokazu Nagai
- Masako Fujioka-Kobayashi
- Go Ohe
- Kanae Hara
- Natsumi Takamaru
- Daisuke Uchida
- Tetsuya Tamatani
- Kenji Fujisawa
- Youji Miyamoto
View Affiliations

Affiliations: Department of Oral Surgery, Subdivision of Molecular Oral Medicine, Division of Integrated Sciences of Translational Research, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan
Published online on: December 31, 2013 https://doi.org/10.3892/or.2013.2959
Pages: 1453-1458

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Salivary gland cancer (SGC) has a comparatively poor prognosis and is prone to frequent recurrence and metastases. Therefore, the development of more effective chemotherapy against SGC is desirable. The aim of the present study was to investigate the antitumour effects of valproic acid (VPA) against SGC in vitro and in vivo. Two human SGC cell lines (HSY and HSG cells) were used in the present study. The effects of VPA on the proliferation of SGC cells in vitro were assessed by MTT assay. Cancer cells treated with VPA were subjected to cell cycle analysis by flow cytometry. In addition, the expression levels of p21 and p27 were examined by real-time RT-PCR to identify the mechanisms of the antitumour effect of VPA on SGC. The effects of VPA on cancer growth in vivo were evaluated in a xenograft model. VPA inhibited the proliferation of SGC cells in a dose-dependent manner in vitro. Degenerated cancer cells were observed at high concentrations of VPA. In the cell cycle analysis, VPA induced cell-growth inhibition and G1 arrest of cell cycle progression in both cancer cell lines in a time- and dose-dependent manner. VPA markedly upregulated the mRNA expression levels of both p21 and p27 in both SGC cell lines in a time-dependent manner. In the xenograft model experiment, VPA treatment markedly inhibited the growth of salivary gland tumours when compared with the growth of the untreated controls. VPA may be a valuable drug in the development of better therapeutic regimens for SGC.

View Figures

View References

1	Speight PM and Barrett AW: Salivary gland tumors. Oral Dis. 8:229–240. 2002. View Article : Google Scholar : PubMed/NCBI
2	Bell D and Hanna EY: Salivary gland cancers: biology and molecular targets for therapy. Curr Oncol Rep. 14:166–174. 2012. View Article : Google Scholar : PubMed/NCBI
3	Hunt JL: An update on molecular diagnostics of squamous and salivary gland tumors of the head and neck. Arch Pathol Lab Med. 135:602–609. 2011.PubMed/NCBI
4	Laurie SA and Licitra L: Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 24:2673–2678. 2006. View Article : Google Scholar
5	Guzzo M, Locati LD, Prott FJ, Gatta G, McGurk M and Licitra L: Major and minor salivary gland tumors. Crit Rev Oncol Hematol. 74:134–148. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bensadoun RJ, Blanc-Vincent MP, Chauvel P, Dassonville O, Gory-Delabaere G and Demard F: Malignant tumours of the salivary glands. Br J Cancer. 84:42–48. 2001. View Article : Google Scholar
7	Yeow WS, Ziauddin MF, Maxhimer JB, et al: Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01. Br J Cancer. 94:1436–1445. 2006. View Article : Google Scholar
8	Shabbeer S, Kortenhorst MS, Kachhap S, Galloway N, Rodriguez R and Carducci MA: Multiple molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo. Prostate. 67:1099–1110. 2007. View Article : Google Scholar : PubMed/NCBI
9	Rosato RR, Almenara JA, Dai Y and Grant S: Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Mol Cancer Ther. 2:1273–1284. 2004.
10	Wolffe AP: Transcription: in tune with the histones. Cell. 77:13–16. 1994. View Article : Google Scholar : PubMed/NCBI
11	Rosato RR, Almenara JA, Yu C and Grant S: Evidence of a functional role for p21^WAF1/CIP1 down-regulation in synergistic antileukemic interactions between the histone deacetylase inhibitor sodium butyrate and flavopiridol. Mol Pharmacol. 65:571–581. 2004.PubMed/NCBI
12	Bug G, Ritter M, Wassmann B, et al: Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer. 104:2717–2725. 2005.PubMed/NCBI
13	Minucci S and Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 6:38–51. 2006. View Article : Google Scholar : PubMed/NCBI
14	Schrump DS and Nguyen DM: Targeting the epigenome for the treatment of thoracic malignancies. Thorac Surg Clin. 16:367–377. 2007. View Article : Google Scholar : PubMed/NCBI
15	Ruefli AA, Ausserlechner MJ, Bernhard D, et al: 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. 98:10833–10838. 2001. View Article : Google Scholar
16	Saunders N, Dicker A, Popa C, Jones S and Dahler A: Histone deacetylase inhibitors as potential anti-skin cancer agents. Cancer Res. 59:399–404. 1999.PubMed/NCBI
17	De Ruijter AJ, van Gennip AH, Caron HN, Kemp S and van Kuilenburg AB: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 370:737–749. 2002.PubMed/NCBI
18	Grozinger CM, Hassig CA and Schreiber SL: Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci USA. 96:4868–4873. 1999. View Article : Google Scholar : PubMed/NCBI
19	Blaheta RA and Cinatl J: Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev. 22:492–511. 2002. View Article : Google Scholar : PubMed/NCBI
20	Yanagawa T, Hayash Y, Nagamine S, Yoshida H, Yura Y and Sato M: Generation of ceils with phenotypes of both intercalated duct-type and myoepithelial cells in human parotid gland adenocarcinoma clonal cells grown in a thymic nude mice. Virchows Arch. 51:187–195. 1986. View Article : Google Scholar
21	Shirasuna K, Sato M and Miyazaki T: Aneoplastic epithelial duct cell line established from an irradiated human salivary gland. Cancer. 48:745–752. 1981. View Article : Google Scholar : PubMed/NCBI
22	Guan XF, Qiu WL, He RG and Zhou XJ: Selection of adenoid cystic carcinoma cell clone highly metastatic to the lung: an experimental study. Int J Oral Maxillofac Surg. 26:116–119. 1997. View Article : Google Scholar : PubMed/NCBI
23	Uchida D, Begum NM, Aimofti A, Kawamata H, Yoshida H and Sato M: Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma. Br J Cancer. 91:1131–1138. 2004.
24	Uchida D, Onoue T, Begum NM, et al: Vesnarinone downregulates CXCR4 expression via upregulation of Kruppel-like factor 2 in oral cancer cells. Mol Cancer. 8:622009. View Article : Google Scholar : PubMed/NCBI
25	Wittenburg LA, Bisson L, Rose BJ, Korch C and Thamm DH: The histone deacetylase inhibitor varproic acid sensitizes human and canine osteosarcoma to doxorubicin. Cancer Chemother Pharmacol. 67:83–92. 2011. View Article : Google Scholar : PubMed/NCBI
26	Huang H, Reed CP, Zhang JS, Shridhar V, Wang L and Smith DI: Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells. Cancer Res. 59:2981–2988. 1999.
27	Sambucetti LC, Fischer DD, Zabludoff S, et al: Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects. J Biol Chem. 274:34940–34947. 1999. View Article : Google Scholar
28	Siavoshian S, Blottiere HM, Cherbut C and Galmiche JP: Butyrate stimulates cyclin D and p21 and inhibits cyclin-dependent kinase2 expression in HT-29 colonic epithelial cells. Biochem Biophys Res Commun. 232:169–172. 1997. View Article : Google Scholar : PubMed/NCBI
29	Erlich RB, Rickwood D, Coman WB, Saunders NA and Guminski A: Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas. Cancer Chemother Pharmacol. 63:381–389. 2008. View Article : Google Scholar : PubMed/NCBI
30	Gottlicher M, Minucci S, Zhu P, et al: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20:6969–6978. 2001. View Article : Google Scholar : PubMed/NCBI
31	Chen CL, Sung J, Cohen M, et al: Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther. 319:533–542. 2006. View Article : Google Scholar : PubMed/NCBI
32	Greenblatt MS, Bennett WP, Hollstein M and Harris CC: Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 54:4855–4878. 1994.PubMed/NCBI
33	Vaziri C, Stice L and Faller DV: Butyrate-induced G1 arrest results from p21-independent disruption of retinoblastoma protein-mediated signals. Cell Growth Differ. 9:465–474. 1998.PubMed/NCBI
34	Sidana A, Wang M, Shabbeer S, et al: Mechanism of growth inhibition of prostate cancer xenografts by valproic acid. J Biomed Biotechnol. 2012:1803632012. View Article : Google Scholar : PubMed/NCBI