Top

Published in:

01-04-2010 | PRECLINICAL STUDIES

The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines

Authors: Brigette B.Y. Ma, Fion Sung, Qian Tao, Fan Fong Poon, Vivian W. Lui, Winnie Yeo, Stephen L. Chan, Anthony T.C. Chan

Published in: Investigational New Drugs | Issue 2/2010

Summary

The activity of the histone deacetylase inhibitor PXD101 was investigated in three hepatocellular carcinoma (HCC) cell lines. PXD101was found to inhibit cell growth at a dose-dependent manner and induce histone acetylation in PLC/PRF/5, Hep3B and HepG2 cells. In PLC/PRF/5 and Hep3B cells which express hepatitis B-related genes (HBx, HBc and HBc), treatment with PXD101 resulted in apoptosis without a significant effect on viral gene expression. Exposure to PXD101 for up to 48 h had varying effects on the expression of 12 cellular genes with tumor suppressor functions, including p21, SOCS1, CMTM5, RASAL1, DLEC1, SFRP (-1, -2, -4 and -5), ADAMTS (-8 and -9). This study provided the basis for a phase II clinical trial of PXD101 in inoperable hepatitis-B associated HCC.

Bosch FX, Ribes J, Diaz M, Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5):S5–S16. doi:10.1053/j.gastro.2004.09.011 CrossRefPubMed

Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C (2006) Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis. Oncogene 25(27):3823–3833. doi:10.1038/sj.onc.1209559 CrossRefPubMed

Roncalli M, Bruni B, Laghi L, Destro A, Di Gioia S, Gennari L, Tommasini M, Malesci A, Coggi G (2002) Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Hepatology 36(2):427–432. doi:10.1053/jhep.2002.34852 CrossRefPubMed

Schagdarsurengin U, Wilkens L, Steinemann D, Flemming P, Kreipe HH, Pfeifer GP, Schlegelberger B, Dammann R (2003) Frequent epigenetic inactivation of the RASSF1A gene in hepatocellular carcinoma. Oncogene 22(12):1866–18710. doi:10.1038/sj.onc.1206338 CrossRefPubMed

Nomoto S, Kinoshita T, Kato K, Otani S, Kasuya H, Takeda S, Kanazumi N, Sugimoto H, Nakao A (2007) Hypermethylation of multiple genes as clonal markers in multicentric hepatocellular carcinoma. Br J Cancer 97(9):1260–1265. doi:10.1038/sj.bjc.6604016 CrossRefPubMed

Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG (2001) SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28(1):29–35. doi:10.1038/88225 CrossRefPubMed

Matsumura T, Makino R, Mitamura K (2001) Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res 7(3):594–599PubMed

Chiba T, Yokosuka O, Arai M, Tada M, Fukai K, Imazeki F, Kato M, Seki N, Saisho H (2004) Identification of genes up-regulated by histone deacetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells. J Hepatol 41(3):436–445. doi:10.1016/j.jhep.2004.05.018 CrossRefPubMed

Dannenberg L, Edenberg HJ (2006) Epigenetics of gene expression in human hepatoma cells: expression profiling the response to inhibition of DNA methylation and histone deacetylation. BMC Genomics 7:181. doi:10.1186/1471-2164-7-181 CrossRefPubMed

10.

Venturelli S, Armeanu S, Pathil A, Hsieh CJ, Weiss TS, Vonthein R, Wehrmann M, Gregor M, Lauer UM, Bitzer M (2007) Epigenetic combination therapy as a tumor-selective treatment approach for hepatocellular carcinoma. Cancer 109(10):2132–2141. doi:10.1002/cncr.22652 CrossRefPubMed

11.

Qian X, LaRochelle WJ, Ara G, Wu F, Petersen KD, Thougaard A, Sehested M, Lichenstein HS, Jeffers M (2006) Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies. Mol Cancer Ther 5(8):2086–2095. doi:10.1158/1535-7163.MCT-06-0111 CrossRefPubMed

12.

Tumber A, Collins LS, Petersen KD, Thougaard A, Christiansen SJ, Dejligbjerg M, Jensen PB, Sehested M, Ritchie JW (2006) The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol 60(2):275–283. doi:10.1007/s00280-006-0374-7 CrossRefPubMed

13.

Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ, La Thangue NB, Brown R (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2(8):721–728PubMed

14.

Seng TJ, Low LS, Li H, Cui Y, Goh HK, Wong ML, Srivastava S, Sidransky D, Califano J, Steenbergen RD, Rha SY, Tan J, Hsieh WS, Ambinder RF, Lin X, Chan AT, Tao Q (2007) The major 8p22 tumor suppressor DLC is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal and cervical carcinoma. Oncogene 26(6):934–944CrossRefPubMed

15.

Chiba T, Yokosuka O, Fukai K, Kojima H, Tada M, Arai M, Imazeki F, Saisho H (2004) Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology 66(6):481–491. doi:10.1159/000079503 CrossRefPubMed

16.

Herold C, Ganslmayer M, Ocker M, Hermann M, Geerts A, Hahn EG, Schuppan D (2002) The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells. J Hepatol 36(2):233–240. doi:10.1016/S0168-8278(01)00257-4 CrossRefPubMed

17.

Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, Lauer UM, Bitzer M (2006) HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology 43(3):425–434. doi:10.1002/hep.21054 CrossRefPubMed

18.

Laurent-Puig P, Zucman-Rossi J (2006) Genetics of hepatocellular tumors. Oncogene 25(27):3778–37860. doi:10.1038/sj.onc.1209547 CrossRefPubMed

19.

Herath NI, Leggett BA, MacDonald GA (2006) Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 21(1 Pt 1):15–21. doi:10.1111/j.1440-1746.2005.04043.x CrossRefPubMed

20.

Georgiadis KE, Hirohata S, Seldin MF, Apte SS (1999) ADAM-TS8, a novel metalloprotease of the ADAM-TS family located on mouse chromosome 9 and human chromosome 11. Genomics 62(2):312–315. doi:10.1006/geno.1999.6014 CrossRefPubMed

21.

Lo PH, Leung AC, Kwok CY, Cheung WS, Ko JM, Yang LC, Law S, Wang LD, Li J, Stanbridge EJ, Srivastava G, Tang JC, Tsao SW, Lung ML (2007) Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9. Oncogene 26(1):148–157. doi:10.1038/sj.onc.1209767 CrossRefPubMed

22.

Jin H, Wang X, Ying J, Wong AH, Cui Y, Srivastava G, Shen ZY, Li EM, Zhang Q, Jin J, Kupzig S, Chan AT, Cullen PJ, Tao Q (2007) Epigenetic silencing of a Ca(2+)-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers. Proc Natl Acad Sci U S A 104(30):12353–12358. doi:10.1073/pnas.0700153104 CrossRefPubMed

23.

Wakabayashi K, Saito H, Kaneko F, Nakamoto N, Tada S, Hibi T (2005) Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor. Int J Oncol 26(1):233–239PubMed

24.

Ying J, Srivastava G, Gao Z, Zhang X, Murray P, Ambinder R, Tao Q (2004) Promoter hypermethylation of the cyclin-dependent kinase inhibitor (CDKI) gene p21WAF1/CIP1/SDI1 is rare in various lymphomas and carcinomas. Blood 103(2):743–746. doi:10.1182/blood-2003-09-3193 CrossRefPubMed

25.

Shih YL, Hsieh CB, Lai HC, Yan MD, Hsieh TY, Chao YC, Lin YW (2007) SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway. Int J Cancer 121(5):1028–1035. doi:10.1002/ijc.22750 CrossRefPubMed

26.

Lee JL, Chang CJ, Wu SY, Sargan DR, Lin CT (2004) Secreted frizzled-related protein 2 (SFRP2) is highly expressed in canine mammary gland tumors but not in normal mammary glands. Breast Cancer Res Treat 84(2):139–149. doi:10.1023/B:BREA.0000018412.83348.ff CrossRefPubMed

27.

Shao L, Cui Y, Li H, Liu Y, Zhao H, Wang Y, Zhang Y, Ng KM, Han W, Ma D, Tao Q (2007) CMTM5 exhibits tumor suppressor activities and is frequently silenced by methylation in carcinoma cell lines. Clin Cancer Res 13(19):5756–5762. doi:10.1158/1078-0432.CCR-06-3082 CrossRefPubMed

28.

Qiu GH, Salto-Tellez M, Ross JA, Yeo W, Cui Y, Wheelhouse N, Chen GG, Harrison D, Lai P, Tao Q, Hooi SC (2008) The tumor suppressor gene DLEC1 is frequently silenced by DNA methylation in hepatocellular carcinoma and induces G1 arrest in cell cycle. J Hepatol 48(3):433–441. doi:10.1016/j.jhep.2007.11.015 CrossRefPubMed

29.

Xiong Y, Dowdy SC, Podratz KC, Jin F, Attewell JR, Eberhardt NL, Jiang SW (2005) Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells. Cancer Res 65(7):2684–2689. doi:10.1158/0008-5472.CAN-04-2843 CrossRefPubMed

30.

Duan HHC, Boxer LM (2005) Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol 25(5):1608–1619. doi:10.1128/MCB.25.5.1608-1619.2005 CrossRefPubMed

31.

Wu CG, Forgues M, Valerie K, Farnsworth J, Markin RS, Wang XW (2001) Distinctive gene expression profiles associated with Hepatitis B virus x protein. Oncogene 20(28):3674–3682. doi:10.1038/sj.onc.1204481 CrossRefPubMed

32.

Park IY, Yu E, Suh DJ, Chung YH, Lee JH, Surzycki SJ, Lee YI (2007) Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology 132(4):1476–1494. doi:10.1053/j.gastro.2007.01.034 CrossRefPubMed

33.

Chen JY, Lee CS, Chen DS, Zuckerman AJ, Harrison TJ (1988) Detection of hepatitis B virus DNA in hepatocellular carcinoma: methylation of integrated viral DNA. J Virol Methods 19(3):257–263. doi:10.1016/0166-0934(88)90020-1 CrossRefPubMed

34.

Miyoshi E, Fujii J, Hayashi N, Ueda K, Towata T, Fusamoto H, Kamada T (1992) Enhancement of hepatitis-B surface-antigen expression by 5-azacytidine in a hepatitis-B-virus-transfected cell line. Int J Cancer 52(1):137–140. doi:10.1002/ijc.2910520124 CrossRefPubMed

35.

Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, Hui P, Leung NW, Zee B, Johnson PJ (2000) Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 62(3):299–307. doi:10.1002/1096-9071(200011)62:3<299::AID-JMV1>3.0.CO;2-0 CrossRefPubMed

36.

Yeo W, Ma B, Hui P, Chan L, Mo F, Yu S, Ho S, Koh J, Chan AT, Goh B (2007) A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma. ASCO Annual Meeting Proceedings Part I 25(18S):15081

Title: The preclinical activity of the histone deacetylase inhibitor PXD101 (belinostat) in hepatocellular carcinoma cell lines
Authors: Brigette B.Y. Ma
Fion Sung
Qian Tao
Fan Fong Poon
Vivian W. Lui
Winnie Yeo
Stephen L. Chan
Anthony T.C. Chan
Publication date: 01-04-2010
Publisher: Springer US
Published in: Investigational New Drugs / Issue 2/2010
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-009-9219-7

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Summary

Please log in to get access to this content

Other articles of this Issue 2/2010

Comparison of the cytotoxic effect of lapachol, α-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells

N-4-iodophenyl-N′-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles

F84, a quinazoline derivative, exhibits high potent antitumor activity against human gynecologic malignancies

Phase IB trial of oral talactoferrin in the treatment of patients with metastatic solid tumors

Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors

The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug

Keynote webinar | Spotlight on antibody–drug conjugates in cancer