Apicidin, an inhibitor of histone deacetylase, prevents H-ras-induced invasive phenotype

Kim, Mi-Sung; Son, Miwon; Kim, Won-Bae; Park, Young In; Moon, Aree

doi:10.1016/s0304-3835(00)00465-1

Cited by 60 publications

(42 citation statements)

References 17 publications

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“…A number of genes with proposed functions in the invasion process have been shown to have altered expression after treatment with HDAC-inhibitors. Caveolin-1, MMP-2 and urokinase have been found to be downregulated, 10,18,24,25 whereas the MMP inhibitors TIMP-1 and TIMP-2 are upregulated by butyrate. 26 Although some apoptosis has been observed in cancer cells after long exposures to 2 mM phenylbutyrate, 5,7,12 we do not believe that induction or commitment to apoptosis is responsible for the loss of invasiveness of these cells after 24-hr incubations with phenylbutyrate.…”

Section: Discussionmentioning

confidence: 99%

Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay

Dyer

Paulsen

Markwart

et al. 2002

Intl Journal of Cancer

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Histone deacetylase inhibitors, such as phenylbutyrate, are currently undergoing clinical trials as potential anticancer agents. Phenylbutyrate can induce cell differentiation and apoptosis in a number of cancer cell types and can act in synergy with ionizing radiation and chemotherapy to induce apoptosis. We used the sea urchin embryo basement membrane invasion assay to show that phenylbutyrate potently inhibited the invasive properties of both prostate and breast cancer cells at clinically achievable doses. This inhibition was dose-dependent and persisted for at least 24 hr after the drug was removed. These results suggest that in addition to activating apoptosis in cancer cells, phenylbutyrate may be used in prevention of metastatic disease. 4 -7 It has been shown that butyrate and phenylbutyrate can act in synergy with radiation 8 -11 or chemotherapy 11,12 to induce cells to undergo apoptosis. Furthermore, some HDAC inhibitors have recently been found to inhibit angiogenesis. 13 The anti-angiogenic properties of HDAC inhibitors may occur through the down regulation of VEGF expression. 10 In our previous study we found that phenylbutyrate reduced the expression of caveolin-1. 10 Although the exact role of caveolin-1 in carcinogenesis is unclear, caveolin-1 is thought to regulate integrin signaling 14 and high expression of caveolin-1 is associated with a metastatic phenotype in breast and prostate cancer. [15][16][17] In addition to reducing caveolin-1 expression, phenylbutyrate has been found to reduce the expression of the invasion-related plasminogen activator, urokinase, in glioma cells 18 and reduce the invasiveness of cancer cells in artificial matrigel chamber invasion assays. 18,19 We explored the ability of phenylbutyrate to block the invasiveness of metastatic prostate and breast cancer cells using the sea urchin embryo basement membrane invasion assay. This invasion assay utilizes the natural occurring, selectively permeable basement membranes of sea urchin embryos (SU-ECM) as invasion substrates. 20,21 The sea urchin embryo basement membrane is functionally analogous to the mammalian basement membranes underlying the epidermis because it is invaded by pigment cells during development. 22 We have shown previously that these SU-ECM invasion substrates can be selectively invaded by metastatic tumor cells. 20 In fact, we have shown that this assay can predict the metastatic potential of cancer cell lines with greater than 99% confidence. 20 We show that phenylbutyrate effectively inhibits the invasiveness of metastatic prostate and breast cancer cells in the SU-ECM invasion assay. MATERIAL AND METHODS Cell cultures and phenylbutyrate treatmentsPC3 and DU-145 cells were obtained from American Type Culture Collection (Manassas, VA) and Steve Ethier, University of Michigan, kindly provided us with the SUM-149 cell line. The PC3 and DU-145 cells were cultured in MEM (Life Technologies, Grand Island, NY) supplemented with 10% FBS (HyClone, Logan, UT), with 1ϫ amino acids, vitamins and antibiotics. SUM-1...

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Section: Discussionmentioning

confidence: 99%

Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay

Dyer

Paulsen

Markwart

et al. 2002

Intl Journal of Cancer

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“…There is increasing evidence suggesting that HDAC inhibitors modulate the expression of cell cycle-progression and apoptosis-regulated genes, preferably in tumor cells to inhibit proliferation and induce apoptotic cell death (10). Although little is known about the cellular effects of HDAC inhibitors in oncogene-transformed mammalian cells, they are considered to be a novel class of anticancer agents (11,12). Based on these results, it is important to understand the Ras-mediated signaling cascade that leads to the increased cell susceptibility to HDAC inhibitors in ras-transformed cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

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Abstract. The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in Hras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1 , in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the upregulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidinmediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

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“…Several studies reported that MMPs are associated with invasion phenotype in tumor cells or Ras-transformed cells. 42,50 We demonstrated that inhibition of MMPs directly block angiogenesis. Inhibition of MMP-9 reduced angiogenesis in human microvascular endothelial cells.…”

Section: S6kmentioning

confidence: 96%

Confirmation of a linkage between H‐Ras and MMP‐13 expression as well as MMP‐9 by chemical genomic approach

Lee

Kim

Lee

et al. 2005

Intl Journal of Cancer

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As farnesylation of the Ras protein by farnesyl transferase is a critical step for the Ras functional activity, the farnesyl transferase inhibitor could affect H-Ras functions and the inhibitors such as arteminolide, SCH66336 and LB42908 completely inhibited Ras-farnesylation. However, they did not induce apoptosis of HRas-transformed cells with concentration for blocking H-Ras farnesylation. To determine the antitumor effects of the inhibitors, it was analyzed through the expression profile of genes, regulated by activated H-Ras or FTIs by using cDNA microarray. On the basis of the results, the relationship between H-Ras and MMPs expression was confirmed by RT-PCR, Western bolt, zymographic analysis and angiogenesis assay. Our results suggested that activation of MMP-13 as well as MMP-9 induced by H-Ras is involved in angiogenesis and with farnesyl transferase inhibitors, in part, exerts their anticancer effects. We confirmed that MMP-13 is a critical H-Ras target gene through chemical genomic approaches with farnesyl transferase inhibitors. ' 2005 Wiley-Liss, Inc.

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Apicidin, an inhibitor of histone deacetylase, prevents H-ras-induced invasive phenotype

Cited by 60 publications

References 17 publications

Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay

Phenylbutyrate inhibits the invasive properties of prostate and breast cancer cell lines in the sea urchin embryo basement membrane invasion assay

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Confirmation of a linkage between H‐Ras and MMP‐13 expression as well as MMP‐9 by chemical genomic approach

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