Characterization of cells resistant to the potent histone deacetylase inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on the SP-B resistance or susceptibility of human leukemia cells

Kanno,Syu-Ichi; Maeda,Naoyuki; Tomizawa,Ayako; Yomogida,Shin; Katoh,Tadashi; Ishikawa,Masaaki

doi:10.3892/ijo.2012.1507

Characterization of cells resistant to the potent histone deacetylase inhibitor spiruchostatin B (SP-B) and effect of overexpressed p21waf1/cip1 on the SP-B resistance or susceptibility of human leukemia cells

Authors:
- Syu-Ichi Kanno
- Naoyuki Maeda
- Ayako Tomizawa
- Shin Yomogida
- Tadashi Katoh
- Masaaki Ishikawa
View Affiliations

Affiliations: Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan, Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan
Published online on: June 6, 2012 https://doi.org/10.3892/ijo.2012.1507
Pages: 862-868
Copyright: © Kanno et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

We previously showed that the B cell leukemia cell line NALM-6 had the highest susceptibility among a number of leukemia cell lines to spiruchostatin B (SP-B), a potent histone deacetylase (HDAC) inhibitor. We also showed that SP-B-induced cytotoxicity depended on induction of apoptosis that was mediated by p21waf1/cip1 expression. In the present study, we generated and characterized a stable, SP-B-resistant NALM-6 cell line (NALM-6/SP-B) by continuous exposure to SP-B, starting with a low SP-B concentration. NALM-6/SP-B cells were also more resistant to FK228, which has a similar chemical structure to SP-B, and were slightly more resistant to the P-gp substrates doxorubicin and vincristine than parental cells, but displayed similar susceptibility to other HDAC inhibitors and to paclitaxel as the parental cells. There was little change in the basal mRNA expression of HDAC1, p53, Bax, Bcl-2, Fas, caspase-3, c-Myc and MDR1 in NALM-6/SP-B compared to parental cells, but the mRNA expression of p21waf1/cip1 was decreased. The introduction of an exogenous p21waf1/cip1 expression vector restored SP-B induction of NALM-6/SP-B cell apoptosis. Moreover, overexpressed p21waf1/cip1 enhanced SP-B induction of the apoptosis of the human erythroleukemia leukemia cell line K562 which is less susceptible to SP-B than NALM-6 cells. These results suggest that downregulation of p21waf1/cip1, which is a characteristic feature of NALM-6/SP-B cells, was important for their resistance to SP-B, and that this SP-B resistance could be overcome by the introduction of exogenous p21waf1/cip1. Furthermore, introduction of p21waf1/cip1 to other leukemia cells such as K562 may enhance their susceptibility to SP-B. This is the first report of the characterization of SP-B-resistant cells and of the effect of overexpressed p21waf1/cip1 on the resistance or susceptibility of human leukemia cells to SP-B.

View Figures

View References

1	Narita K, Kikuchi T, Watanabe K, et al: Total synthesis of the bicyclic depsipeptide HDAC inhibitors spiruchostatins A and B, 5″-epi-spiruchostatin B, FK228 (FR901228) and preliminary evaluation of their biological activity. Chemistry. 15:11174–11186. 2009.PubMed/NCBI
2	Ocker M and Schneider-Stock R: Histone deacetylase inhibitors: signalling towards p21cip1/waf1. Int J Biochem Cell Biol. 39:1367–1374. 2007. View Article : Google Scholar : PubMed/NCBI
3	Xiong Y, Zhang H and Beach D: D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 71:505–514. 1992. View Article : Google Scholar : PubMed/NCBI
4	Han JW, Ahn SH, Kim YK, et al: Activation of p21(WAF1/Cip1) transcription through Sp1 sites by histone deacetylase inhibitor apicidin: involvement of protein kinase C. J Biol Chem. 276:42084–42090. 2001. View Article : Google Scholar : PubMed/NCBI
5	Fournel M, Trachy-Bourget MC, Yan PT, et al: Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are anti-proliferative against human tumors. Cancer Res. 62:4325–4330. 2002.
6	Archer SY, Meng S, Shei A and Hodin RA: p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci USA. 95:6791–6796. 1998. View Article : Google Scholar : PubMed/NCBI
7	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
8	Kanno SI, Maeda N, Tomizawa A, Yomogida S, Katoh T and Ishikawa M: Involvement of p21^waf1/cip1 expression in the cytotoxicity of the potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells. Int J Oncol. 40:1391–1396. 2012.
9	Szakacs G, Annereau JP, Lababidi S, et al: Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell. 6:129–137. 2004. View Article : Google Scholar : PubMed/NCBI
10	Xiao JJ, Huang Y, Dai Z, et al: Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 314:467–475. 2005.PubMed/NCBI
11	Yamada H, Arakawa Y, Saito S, Agawa M, Kano Y and Horiguchi-Yamada J: Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile. Leuk Res. 30:723–734. 2006. View Article : Google Scholar
12	Matsubara H, Watanabe M, Imai T, et al: Involvement of extracellular signal-regulated kinase activation in human osteosarcoma cell resistance to the histone deacetylase inhibitor FK228 [(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dit hia-5,8,20,23-tetraazabicyclo[8.7.6] tricos-16-ene-3,6,9,19,22-pentone]. J Pharmacol Exp Ther. 328:839–848. 2009.PubMed/NCBI
13	Imesch P, Dedes KJ, Furlato M, Fink D and Fedier A: MLH1 protects from resistance acquisition by the histone deacetylase inhibitor trichostatin A in colon tumor cells. Int J Oncol. 35:631–640. 2009.PubMed/NCBI
14	Dedes KJ, Dedes I, Imesch P, von Bueren AO, Fink D and Fedier A: Acquired vorinostat resistance shows partial cross-resistance to ‘second-generation’ HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. Anticancer Drugs. 20:321–333. 2009.PubMed/NCBI
15	Takizawa T, Watanabe K, Narita K, Oguchi T, Abe H and Katoh T: Total synthesis of spiruchostatin B, a potent histone deacetylase inhibitor, from a microorganism. Chem Commun (Camb). 1677–1679. 2008. View Article : Google Scholar : PubMed/NCBI
16	Kanno S, Kakuta M, Kitajima Y, et al: Preventive effect of trimidox on oxidative stress in U937 cell line. Biol Pharm Bull. 30:994–998. 2007. View Article : Google Scholar : PubMed/NCBI
17	Kanno S, Hiura T, Ohtake T, et al: Characterization of resistance to cytosine arabinoside (Ara-C) in NALM-6 human B leukemia cells. Clin Chim Acta. 377:144–149. 2007. View Article : Google Scholar : PubMed/NCBI
18	Kanno S, Higurashi A, Watanabe Y, Shouji A, Asou K and Ishikawa M: Susceptibility to cytosine arabinoside (Ara-C)-induced cytotoxicity in human leukemia cell lines. Toxicol Lett. 152:149–158. 2004.PubMed/NCBI
19	Song JH, Choi CH, Yeom HJ, Hwang SY and Kim TS: Monitoring the gene expression profiles of doxorubicin-resistant acute myelocytic leukemia cells by DNA microarray analysis. Life Sci. 79:193–202. 2006. View Article : Google Scholar : PubMed/NCBI
20	Li W, Fan J, Banerjee D and Bertino JR: Overexpression of p21(waf1) decreases G2-M arrest and apoptosis induced by paclitaxel in human sarcoma cells lacking both p53 and functional Rb protein. Mol Pharmacol. 55:1088–1093. 1999.PubMed/NCBI
21	Ahmed W, Rahmani M, Dent P and Grant S: The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) blocks paclitaxel-induced G2M arrest and attenuates mitochondrial injury and apoptosis in p53-null human leukemia cells. Cell Cycle. 3:1305–1311. 2004. View Article : Google Scholar
22	Fiskus W, Rao R, Fernandez P, et al: Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells. Blood. 112:2896–2905. 2008. View Article : Google Scholar : PubMed/NCBI
23	Bandyopadhyay D, Mishra A and Medrano EE: Overexpression of histone deacetylase 1 confers resistance to sodium butyrate-mediated apoptosis in melanoma cells through a p53-mediated pathway. Cancer Res. 64:7706–7710. 2004. View Article : Google Scholar : PubMed/NCBI
24	Condorelli F, Gnemmi I, Vallario A, Genazzani AA and Canonico PL: Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol. 153:657–668. 2008. View Article : Google Scholar : PubMed/NCBI
25	Vrana JA, Decker RH, Johnson CR, et al: Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. Oncogene. 18:7016–7025. 1999. View Article : Google Scholar : PubMed/NCBI
26	Insinga A, Monestiroli S, Ronzoni S, et al: Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med. 11:71–76. 2005. View Article : Google Scholar : PubMed/NCBI
27	Sasakawa Y, Naoe Y, Inoue T, et al: Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo. Cancer Lett. 195:161–168. 2003. View Article : Google Scholar : PubMed/NCBI
28	Peart MJ, Smyth GK, van Laar RK, et al: Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA. 102:3697–3702. 2005. View Article : Google Scholar : PubMed/NCBI
29	Imai T, Adachi S, Nishijo K, et al: FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells. Oncogene. 22:9231–9242. 2003. View Article : Google Scholar : PubMed/NCBI
30	Liu S, Bishop WR and Liu M: Differential effects of cell cycle regulatory protein p21(WAF1/Cip1) on apoptosis and sensitivity to cancer chemotherapy. Drug Resist Updat. 6:183–195. 2003. View Article : Google Scholar : PubMed/NCBI
31	Law JC, Ritke MK, Yalowich JC, Leder GH and Ferrell RE: Mutational inactivation of the p53 gene in the human erythroid leukemic K562 cell line. Leuk Res. 17:1045–1050. 1993. View Article : Google Scholar : PubMed/NCBI
32	Filippini G, Griffin S, Uhr M, et al: A novel flow cytometric method for the quantification of p53 gene expression. Cytometry. 31:180–186. 1998. View Article : Google Scholar : PubMed/NCBI