Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Kouraklis, Gregory; Theocharis, S.

doi:10.3892/or.15.2.489

Cited by 52 publications

(54 citation statements)

References 47 publications

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“…Clinical studies indicate that HDAC inhibitors such as 2 are effective therapies for human cancer, 22 but dose-limiting toxicity remains a problem. 6,23 HDAC inhibitors partially restore normal cell cycle and apoptotic functions in human tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

et al. 2008

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A series of polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) were synthesized and evaluated as isoform-selective histone deacetylase (HDAC) inhibitors. These analogues contain a polyamine chain to increase affinity for chromatin and facilitate cellular import. Seven PAHAs inhibited HDAC >50% (1 µM), and two PABAs inhibited HDAC >50% (5 µM). Compound 17 increased acetylated α-tubulin in HCT116 colon tumor cells 253-fold but only modestly increased p21 waf1 and acetylated histones 3 and 4, suggesting that 17 selectively inhibits HDAC 6. PABA 22 alone minimally increased p21 waf1 and acetylated histones 3 and 4 but caused dose-dependent increases in p21 waf1 in combination with 0.1 µM 5-azadeoxycytidine. Finally, 22 appeared to be a substrate for the polyamine transport system. None of these compounds were cytotoxic at 100 µM. PAHAs and PABAs exhibit strikingly different cellular effects from SAHA and have the potential for use in combination antitumor therapies with reduced toxicity.

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Section: Discussionmentioning

confidence: 99%

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

et al. 2008

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“…Previous in vitro data indicates the combination of HDACis, such as SAHA and valproic acid, and DNA methyltransferase inhibitors, such as decitabine, resulted in increased cytotoxic effects (4,7,10). To extend these studies to a benzamide derivative HDACi -MS-275, the potential, synergistic cytotoxicity of the combination of MS-275 and 5-azacytidine was investigated.…”

Section: The Combined Exposure Of Ms-275 and 5-azacytidine Increases mentioning

confidence: 99%

“…Thus, it can be used as a tool to discern between relative contributions of these HDACs to cancer types. In addition, MS-275 has been evaluated in Phase I/II clinical trials to treat acute leukemias and solid tumors (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Gao¹,

Mobley²,

Miller³

et al. 2008

Leukemia Research

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Epigenetic modifiers are currently in clinical use for various tumor types. Recently, numerous studies supporting the combination of histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors have emerged, encouraging early clinical trials of these agents together. Here we show that MS-275, an HDACi, and 5-azacytidine, a methyltransferase inhibitor, display synergistic cytotoxicity and apoptosis in AML and ALL cells. Intracellular production of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, is a novel marker for this synergism in ALL cells. These data suggest that assessment of oxidative stress can serve as a marker of the concerted action of MS-275 and 5-azacytidine.

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“…Many in vitro and animal studies have demonstrated that they can induce differentiation and apoptosis, inhibit cell proliferation, and exert immune stimulatory and antiangiogenic activities in tumor cells (1,2). Additionally, HDIs have been shown to enhance the anti-neoplastic efficiency of other therapeutic regimens, such as ionizing radiation or chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells

Sonnemann

Hüls²,

Sigler³

et al. 2008

Oncol Rep

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Abstract. Histone deacetylase inhibitors (HDIs) as well as non-steroidal anti-inflammatory drugs including aspirin show promise as antineoplastic agents. The treatment with both HDIs and aspirin can result in hyperacetylation of proteins. In this study, we investigated whether HDIs and aspirin interacted in inducing anticancer activity and histone acetylation. We found that the HDIs, suberoylanilide hydroxamic acid and sodium butyrate, and aspirin cooperated to induce cell death in the ovarian cancer cell line, A2780. The effect was synergistic, as evidenced by CI-isobologram analysis. However, aspirin had no effect on histone acetylation, neither in the absence nor presence of HDIs. To gain insight into the mechanism underlying the synergistic action of HDIs and aspirin, we employed the deacetylated metabolite of aspirin, salicylic acid, and the cyclooxygenase-1-and -2-selective inhibitors, SC-560 and NS-398, respectively. We found that HDIs and salicylic acid interacted synergistically, albeit less efficiently than HDIs and aspirin, to induce cancer cell death, suggesting that the acetyl and the salicyl moiety contributed to the cooperative interaction of aspirin with HDIs. SC-560 and NS-398 had little effect both when applied alone or in conjunction with HDIs, indicating that the combinatorial effect of HDIs and aspirin was not the result of cyclo-oxygenase inhibition. In conclusion, our study demonstrates that HDIs and aspirin synergize to induce cancer cell death and, thus, provides a rationale for a more in-depth exploration into the potential of combining HDIs and aspirin as a strategy for anticancer therapy.

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Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

Cited by 52 publications

References 47 publications

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Polyaminohydroxamic Acids and Polyaminobenzamides as Isoform Selective Histone Deacetylase Inhibitors

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Histone deacetylase inhibitors and aspirin interact synergistically to induce cell death in ovarian cancer cells

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