The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines

Batova, Ayse; Shao, Li‐en; Diccianni, Mitchell B.; Yu, Alice L.; Tanaka, Tetsuya; Rephaeli, Ada; Nudelman, Abraham; Yu, John

doi:10.1182/blood-2002-02-0567

Cited by 65 publications

(46 citation statements)

References 32 publications

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“…29,33,34 HL60/ADR, the doxorubicin-resistant clone of HL60 obtained by the transfection of the MDR-1 gene, was equally sensitive to pivaloyloxymethyl butylate-induced cytotoxicity as the parental cells. 35 Overall, these data suggest that several types of HDACIs can overcome the drug resistance of the cells expressing P-gp and/or MRP1. However, we revealed that FK228 and apicidin showed strong cross-resistance against the drug-resistant clones expressing P-gp and MRP1, which independently contributed to their resistance mechanisms.…”

Section: Discussionmentioning

confidence: 93%

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

Okada

Tanaka

Nakatani

et al. 2005

Intl Journal of Cancer

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Despite recent improvements in multimodal therapies for osteosarcoma (OS) and Ewing's family of tumors (EFTs), the prognosis of relapsed cases remains very poor because of the resistance to chemotherapy. Histone deacetylase inhibitors (HDACIs), including members of the cyclic tetrapeptide family such as FK228 and apicidin, are novel antitumor agents that can induce cell cycle arrest and apoptosis in various cancer cells. HDACIs also exhibit potent antitumor effects on OS and EFTs. However, to date there have been no studies to our knowledge reporting the effects of HDACIs on drug-resistant OS and EFTs. Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin. A P-gp inhibitor (verapamil) and an MRP1 inhibitor (MK571) could independently reverse the resistance to FK228 and apicidin in the drug-resistant clones. Moreover, the combination of verapamil and MK571 could enhance HDACI-induced cell number reduction in drug-resistant clones to a similar extent as that in their parental clones. Although these findings suggest the difficulty in treating drug-resistant tumors expressing P-gp and/or MRP1 with these HDACIs, the combination of P-gp and MRP1 inhibitors might reverse the resistance to the HDACIs in the treatment of those tumors. Because HDACIs are potent and promising antitumor drugs and seem to be close to clinical use, it is necessary to pay attention to the resistance mechanisms against HDACIs. ' 2005 Wiley-Liss, Inc.Key words: HDAC inhibitor; FK228 (Depsipeptide, FR901228); apicidin; P-gp; MRP1 Histone deacetylase inhibitors (HDACIs) are novel and promising antitumor agents. Previous studies demonstrated that HDACIs can activate transcription of specific genes via the accumulation of histone acetylation and subsequently cause a variety of phenotypic changes, including cell cycle arrest, morphologic reversion of transformed cells, differentiation and apoptosis. 1-3 A number of HDACIs exert antitumor effects on several cancers and are under clinical trials. Among them, FK228, a cyclic tetrapeptide acting as an HDACI, has been reported to show strong antitumor effects on various types of malignant tumors. 4 FK228 is under phase II clinical trials for relapsed or refractory cases of leukemia and advanced or metastatic colorectal cancer. Apicidin is a novel HDACI and another member of the cyclic tetrapeptide family with a potent broad spectrum of antiproliferative activity against various cancer cell lines, 5,6 and its structure is related to FK228.Osteosarcoma (OS) and Ewing's family of tumors (EFTs) are the two most frequent primary malignant bone tumors in childhood and adolescence. Despite marked improvements in the multimodal therapies and outcome, systemic relapses are observed in approximately 30-40% of cases and prognosis is very poor.7-10 It has been reported...

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Section: Discussionmentioning

confidence: 93%

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

Okada

Tanaka

Nakatani

et al. 2005

Intl Journal of Cancer

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“…Butyrates have been under extensive clinical evaluation in both hematological malignancies and solid tumors. Butanoic acid or its prodrug pivaloyl oxymethyl butyrate (AN-9) is currently undergoing clinical trials after it showed 10-fold more potent activity than SB in leukemia tumor cell lines (Batova et al, 2002;Patnaik et al, 2002;. The antineoplastic activity of AN-9 stems from rapid hydrolysis and release of butyrate, permitting efficient delivery to subcellular targets (Zimra et al, 1997(Zimra et al, , 2000.…”

Section: Short-chain Fatty Acidsmentioning

confidence: 99%

Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review

Acharya

Sparreboom²,

Venitz³

et al. 2005

Mol Pharmacol

221

172

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The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.In eukaryotic cells, DNA has been conserved over evolution in a condensed and densely packed higher order structure called chromatin. Chromatin, present in the interphase nucleus, is composed of regular repeating units of nucleosomes, which represent the principal protein-nucleic acid relationship. The major components of chromatin are nucleic acids (DNA and RNA), which are negatively charged; associated proteins, including histones, that are positively charged at neutral pH; and nonhistone chromosomal proteins, which are acidic at neutral pH. Within the nucleus, chromatin can exists in two different forms: heterochromatin, which is highly compact and transcriptionally inactive, or euchromatin, which is loosely packed and accessible to RNA polymerases for involvement in transcriptional processes and gene expression. A nucleosome is a complex of 146 nucleotide base pairs of DNA wrapped around the core histone octamer that helps organize chromatin. The histone octamer is composed of two copies each of H2A, H2B, H3, and H4 proteins, which are very basic, mainly because of positively charged amino-terminal side chains rich in the amino acid lysine. Post-translational and other changes in chromatin, such as acetylation/deacetylation at lysine residues, methylation at lysine or arginine residues, phosphorylation at serine resides, ubiquitylation at lysines, and/or ADP ribosylation, are mediated by chemical modification of various sites on N-terminal tail .The structural modification of histones is regulated mainly by acetylation/deacetylation of the N-terminal tail and is crucial in modulating gene expression, because it affects the interaction of DNA with transcription-regulatory non-nucleoArticle, publication date, and citation information can be found at

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“…While AN-9 displayed synergy with DNA-interacting agents, BA itself did not. 23 The synergistic effects between AN-9 and DNA-disrupting agents have been observed in murine monocytic leukemia cells and the combination of AN-9 with daunorubicin led to a significant increase in survival of mice inoculated with acute monocytic leukemia cells. 24 increased the level of doxorubicin-and mitoxantrone-DNA adducts and affected in a synergistic manner their antiproliferative activity in neuroblastoma and breast cell lines.…”

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confidence: 99%

In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

Rephaeli

Blank-Porat

Tarasenko

et al. 2005

Intl Journal of Cancer

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AN-7, a prodrug of butyric acid, induced histone hyperacetylation and differentiation and inhibited proliferation of human prostate 22Rv1 cancer cells in vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN-7 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25% of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm 3 or death) in the untreated was 52 days, and average tumor volume was 0.8 6 0.18 cm 3 . At the same time, 94.4% of AN-7-treated mice survived and had average tumor volumes of 0.37 6 0.1 cm 3 . PSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with AN-7, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein Bax. Sections taken from AN-7-treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not cause adverse effects and the former exhibited significant anticancer activity, AN-7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients. ' 2005 Wiley-Liss, Inc.Key words: AN-7; histone deacetylase inhibitor; prostate-specific antigen; prodrug; lung metastasis; prostate carcinoma Modification of histones as molecular targets for disease therapy in general, and for cancer therapy in particular, is the subject of intense investigations.1-4 The steady-state level of core histone acetylation, maintained by a dynamic balance between the activity of HATs and HDACs, provides a molecular communication link between chromatin and signal transduction. 5,6 In general, increased levels of histone acetylation lead to relaxation of the chromatin structure, allowing access of transcription factors and increased transcription, while decreased levels of acetylation are associated with repressed transcription.Considerable attention has been focused on developing HDACIs as potential anticancer agents. [1][2][3][4] In cancer cells, HDACIs affect the regulation of gene expression, cell growth, differentiation and apoptosis. A number of substances that display HDACI properties are in preclinical and clinical development, including AN-9 (a derivative of BA), the hydroxamic acid SAHA, trichostatin A, the benzamides MS-275 and CI-994 and the cyclic peptides trapoxin and depsipeptide. [7][8][9][10][11][12] For over a decade, we have studied prodrugs of low m.w. aliphatic acids, primarily BA, as potential anticancer agents. 13-15These compounds undergo esterase-dependent intracellular hydrolysis to release acids and aldehydes. The intracellular metabolic degradation is supported by the observat...

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The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines

Cited by 65 publications

References 32 publications

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

Involvement of P‐glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug‐resistant osteosarcoma and Ewing's sarcoma cells

Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review

In vivo and in vitro antitumor activity of butyroyloxymethyl‐diethyl phosphate (AN‐7), a histone deacetylase inhibitor, in human prostate cancer

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