Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo

Sasakawa, Yuka; Naoe, Yoshinori; Inoue, Takeshi; Sasakawa, Tatsuya; Matsuo, Makoto; Manda, Toshitaka; Mutoh, Seitaro

doi:10.1016/s0304-3835(03)00184-8

Cited by 43 publications

(30 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The given results suggest that an intact p21, Rb and c-myc may have to be present for treatment effect. A similar observation has been made for a novel HDAC inhibitor FK228 (Sasakawa et al, 2003). Still, the given data obviously look only at a very small portion of possibly involved pathways and thus have to be considered as preliminary.…”

Section: Discussionsupporting

confidence: 59%

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

et al. 2004

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACs) are known to exhibit antiproliferative effects on various carcinoma cells. In this study, the in vivo efficiency of two HDACs, sodium butyrate and tributyrin, on prostate cancer growth inhibition were investigated. To gain an insight into the possible underlying pathways, cell culture experiments were performed focusing on the expression of p21, Rb and cmyc. For in vivo testing, prostate cancer cell lines (PC3 and TSU-Pr1) were seeded on the chorioallantois membrane (CAM) and implanted in a xenograft model using nude mice. Standard Western blot analysis was performed for protein expression of p21, Rb and c-myc in HDAC-treated vs untreated prostate cancer cells. Both sodium butyrate and tributyrin had a considerable treatment effect on microtumours on the chicken egg at already very low concentrations of 0.1 mM. Tributyrin-treated tumours showed the strongest effect with 38% apoptotic nuclei in the prostate cancer cell line PC3. In the mouse model, there was almost no difference between sodium butyrate and tributyrin. In untreated animals the tumours were almost double the size 4 weeks after implantation. Tumours of the treatment groups had a significantly lower percentage of Ki-67-positive-stained nuclei. As demonstrated by Western blot analysis, these effects seem to be independent of p53 status and a pathway via p21 -Rb -c-myc is possibly involved. In this study we have demonstrated a substantial in vivo treatment effect, which can be induced by the application of sodium butyrate or the orally applicable tributyrin in human prostate cancer. The given results may provide the rationale to apply these drugs in well-controlled clinical trials in patients being at high risk of recurrence after specific therapy or in patients with locally or distant advanced prostate cancer.

show abstract

Section: Discussionsupporting

confidence: 59%

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

et al. 2004

View full text Add to dashboard Cite

show abstract

“…The effect of HDAC inhibitors on the viability of prostate cancer cells has been poorly studied. Several reports have demonstrated that HDAC inhibitors decrease cell proliferation in various prostate cancer lines (11,12,(24)(25)(26)(27)) and a few studies have shown the induction of apoptosis after exposure to HDAC inhibitors for 2 or more days (11,12,26). In the present study, using LNCaP, DU145 and PC-3 prostate cells, we confirmed inhibition of proliferation of prostate cells by SB.…”

Section: Discussionsupporting

confidence: 83%

Growth of human prostate cancer cells is significantly suppressed in vitro with sodium butyrate through apoptosis

Qiu

Gao²,

Shima³

2011

Oncol Rep

View full text Add to dashboard Cite

Abstract. Histone deacetylase inhibitors (HDACis) have shown significant antiproliferative and apoptotic properties in various types of cancer cells, including prostate cancer cells, and are therefore being evaluated as a treatment modality. However, the mechanism by which sodium butyrate (SB) induces apoptosis is not completely understood. We focused on SB which exists in the intestine and is therefore expected to have less adverse effects. In this study, three prostate cancer cell lines (LNCaP, DU145 and PC-3) were treated in vitro with different concentrations of SB. Cell proliferation was studied by the XTT assay; cell cycle analysis and induction of apoptosis were studied by laser scanning cytometry. Western blot analysis was used to study p21, p27, CDK2, CDK4, CDK6, caspase-3, caspase-7, Fas, FADD, TRADD, Bcl-2 and Bax protein expression. SB inhibited cell growth and induced apoptosis in a concentration-dependent manner in human prostate cancer cells (LNCaP,. Western blot analysis showed dose-dependent increases of p21 levels in DU145 and PC-3 cells, and dose-dependent decreases of CDK2, CDK4, CDK6 and procaspase-3 protein levels in all three prostate cancer cell lines. Bcl-xL was significantly down-regulated in DU145 cells, and Bcl-2 was significantly down-regulated in PC-3 and LNCaP cells. No significant changes were observed in procaspase-7, TRADD and Bax expression, although slight decreases in Fas and FADD expression were seen in all three prostate cancer cell lines. Analysis of cell morphology using laser scanning microscopy detected condensed and fragmented nuclei. In conclusion, SB induces G1 and G2 arrest by increasing p21 expression resulting in CDK2, CDK4 and CDK6 down-regulation. SB potently induced apoptosis, which was accompanied by DNA fragmentation, down-regulated Bcl-2 in LNCaP and PC-3 cells, Bcl-xL in DU145 cells, and down-regulated procaspase-3, but not procaspase-7, in these human prostate cancer cell lines. These results suggest that SB may serve as a new modality for the treatment of hormone refractory prostate cancer. IntroductionProstate cancer has the highest incidence and is the second leading cause of cancer-related deaths among men (1). One out of nine men over 65 years of age is diagnosed with prostate cancer in the United States (2). In Japan, the incidence of prostate cancer is also increasing. Most patients who develop metastatic disease initially respond to androgen deprivation, but ultimately develop androgen-independent disease that results in progressive clinical deterioration and death (3). Therapies commonly used for hormone refractory prostate cancer, such as androgen withdrawal, cytotoxic chemotherapy and radiotherapy are relatively nonselective, highly toxic to normal tissues, and rarely curative (4). There is a great need to develop better mechanism-based therapies for prostate cancer.Accumulating data indicate that many anticancer drugs can cause the death of tumor cells through the induction of apoptosis, which is regarded as the preferred way to manage cancer. ...

show abstract

“…55 HDIs appear to act though a distinct reprogramming of gene expression, which activates genes involved in cell cycle arrest such as p21 WAF1 while repressing genes involved in proliferation such as cyclin D1 and c-Myc. 29,30 We have previously shown that c-Src is also directly repressed by HDIs. 31 Here, we demonstrate that all SFK members expressed in a panel of HCCLs react similarly to HDIs.…”

Section: Discussionmentioning

confidence: 95%

“…26 However, HDIs also acetylate nonhistone proteins such as p53, enhance mRNA stability and repress as many genes as they activate, including cyclin D1 and the proto-oncogene c-Myc. [27][28][29][30] Taken together these observations suggest that the mechanisms associated with HDI-mediated changes in gene expression remain poorly understood.…”

mentioning

confidence: 99%

Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells

Hirsch

Smith-Windsor

Bonham

2005

Intl Journal of Cancer

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDIs) induce cell cycle arrest, differentiation and/or apoptosis in numerous cancer cell types and have shown promise in clinical trials. These agents are particularly novel, given their ability to selectively influence gene expression. Previously, we demonstrated that the HDIs butyrate and trichostatin A (TSA) directly repress c-Src proto-oncogene expression in many cancer cell lines. Activation and/or overexpression of c-Src have been frequently observed in numerous malignancies, especially of the colon. Therefore, our observation was particularly interesting since butyrate is a naturally abundant component of the large intestine and has been suggested to be a cancer-preventive agent. However, c-Src is not the only Src family kinase (SFK) member to be implicated in the development of human cancers, including those of the colon. Therefore, the relative expression levels of known SFKs were examined in a panel of human colon cancer cell lines. We found a surprisingly diverse expression pattern but noted that most cell lines expressed relatively high levels of at least 2 SFKs. When the effects of butyrate and TSA were examined in representative cell lines, the expression of all SFKs was repressed in a dose-and time-dependent manner. Further, detailed examination of Lck, Yes and Lyn demonstrated that this repression had a direct effect on transcription and was independent of new protein synthesis. These results mirror our earlier data obtained with c-Src and suggest that SFKs are a major target of HDIs and likely account in part for the anticancer effects of these promising new drugs. ' 2005 Wiley-Liss, Inc.

show abstract

Effects of FK228, a novel histone deacetylase inhibitor, on tumor growth and expression of p21 and c-myc genes in vivo

Cited by 43 publications

References 21 publications

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

Sodium butyrate and tributyrin induce in vivo growth inhibition and apoptosis in human prostate cancer

Growth of human prostate cancer cells is significantly suppressed in vitro with sodium butyrate through apoptosis

Src family kinase members have a common response to histone deacetylase inhibitors in human colon cancer cells

Contact Info

Product

Resources

About