Butyrate analogue, isobutyramide, inhibits tumor growth and time to androgen‐independent progression in the human prostate LNCaP tumor model

Gleave, Martin E.; Sato, Naohide; Sadar, Marianne D.; Yago, Virginia; Bruchovsky, Nicholas; Sullivan, Lorne D.

doi:10.1002/(sici)1097-4644(19980601)69:3<271::aid-jcb5>3.3.co;2-7

Cited by 14 publications

(21 citation statements)

References 20 publications

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“…These effects are reminiscent of other agents reported to block the proliferation of prostate cancer cells in vitro and in vivo, most notable the histone deactylase inhibitors (HDACi). Using the LNCaP tumour model, sodium butyrate caused G 1 cell-cycle arrest, inhibited LNCaP cell growth and increased PSA gene expression (Kruh, 1982;Gleave et al, 1998). Similar findings with respect to inhibition of cell proliferation and PSA secretion have been reported for vitamin D 3 (Esquenet et al, 1996), calcitriol (Bauer et al, 2003), activin A, (Fujii et al, 2004) and phenylacetate (Walls et al, 1996).…”

Section: Discussionsupporting

confidence: 70%

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

et al. 2009

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Androst-5-ene-3b, 17b-diol (AED) is an adrenal hormone that has been reported to sustain prostate cancer growth after androgen deprivation therapy (ADT). LNCaP cells express a mutated androgen receptor that confers the ability to respond not only to androgen but also to oestrogen and adrenal hormones such as AED, and thus provide a cell line useful for identifying compounds capable of inhibiting AED-stimulated cell growth. We sought to determine whether structurally related steroids could inhibit AED-stimulated LNCaP cell growth in vitro and tumour growth in vivo. We report here the identification of a novel androstane steroid, A considerable amount of research has been directed towards understanding factors that support the growth and expansion of prostate cancer during and after anti-androgen treatment. The observation that androgen deprivation results in increase in AR expression (Scher et al, 2004) highlights the importance of AR in this stage of disease and suggests that other ligands may be capable of binding and activating AR to drive tumour cell growth. It is well documented that mutations in the AR allow castration-resistant prostate cancer cells to utilise a broad spectrum of steroids, whose levels are not affected by anti-androgen therapy (Taplin et al, 1995). These include oestrogen, progesterone, glucocorticoid, and the adrenal hormone androst-5-ene-3b, 17b-diol (AED), a multipotent hormone that is an androgen and oestrogen precursor, with the ability to directly transactivate AR and ER in prostate cancer cells (Miyamoto et al, 1998;Maggiolini et al, 2004). Because AED's central role both as a precursor of DHT and a direct activator of the androgen receptor, we initiated studies to identify an inhibitor of AED signalling in hormonally sensitive tumour cells from a proprietary chemical library based on the structure of AED. Through the course of this work, compounds were identified that inhibited the proliferation of LNCaP cells stimulated by AED in vitro. Subsequent work to identify the most suitable pharmaceutical from this series of compounds resulted in the identification of HE3235 (17a-ethynyl-5a-androstan-3a, 17b-diol). Here, we present results showing that HE3235 blocks the growth of LNCaP cells by inducing apoptosis. Tumour studies have confirmed the in vivo activity of HE3235 against AED-stimulated LNCaP tumour cells. MATERIALS AND METHODS Synthesis of HE3235HE3235 was synthesised by reacting trimethylsilylazine with androsterone (DGP, Shanghai, China) in refluxing acetonitrile using saccharin catalyst. The trimethylsilyl-protected intermediate was subsequently reacted with ethynyltrimethylsilane activated with n-butyl lithium in tetrahydrofuran. The crude product was then recovered by slow addition of water to quench the reaction and filtration of the crude precipitate. The reaction product was purified to 499% pure HE3235 with a 67% of overall yield. LNCaP proliferation assayLNCaP-FGC, PC3, and DU145 cells were obtained from the American Type Tissue Collection (ATTC, Manassas, VA, USA). T...

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Section: Discussionsupporting

confidence: 70%

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

et al. 2009

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“…It is a potent growth inhibitor and initiates cell differentiation in several cell types, including breast cancer cells in vitro (Coradini et al 1997, Velázquez et al 1997, Gleave et al 1998, Yamamoto et al 1998. Although the molecular mechanisms by which butyrate exerts its effects are still unclear, it is known to induce a number of alterations within the nucleus, including histone hyperacetylation (de Haan et al 1986, Archer & Hodin 1999.…”

Section: Introductionmentioning

confidence: 99%

Effects of sodium butyrate on expression of members of the IGF-binding protein superfamily in human mammary epithelial cells

Tsubaki¹,

Choi²,

Ingermann³

et al. 2001

Journal of Endocrinology

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Dietary factors play an important role in both the development and prevention of human cancers, including breast carcinoma. One dietary micronutrient, sodium butyrate (NaB), is a major end product of dietary starch and fiber, produced naturally during digestion by anaerobic bacteria in the cecum and colon. NaB is a potent growth inhibitor and initiates cell differentiation for many cell types in vitro. In this study, we investigated the effects of NaB on three human mammary epithelial cells and regulation of the IGF axis, specifically, IGF-binding protein-3 (IGFBP-3), a known growth regulator in human mammary cells, and IGFBP-related protein 2 (IGFBP-rP2)/connective tissue growth factor. NaB inhibited DNA synthesis, as measured by [ 3 H]thymidine incorporation, in estrogen-responsive (MCF-7) and estrogen-non-responsive (Hs578T) breast cancer cells, and normal human mammary epithelial cells (HMEC) to a similar degree (up to 90% inhibition at 1-10 mM concentrations). Treatment of cells with NaB induced histone hyperacetylation, suggesting that NaB exerts its biological effects, at least in part, as a histone deacetylase inhibitor in mammary epithelial cells. Treatment of Hs578T cells with NaB caused an induction of apoptotic cell death. NaB treatment resulted in increased levels of p21Waf1/Cip1 mRNA and protein in Hs578T cells and distinct upregulation of p27 Kip1 in HMEC, suggesting that NaB activates different genes involved in cell cycle arrest, depending upon the cell type. In the same context, among the IGFBP superfamily members tested, NaB specifically upregulated the expression of IGFBP-3 and IGFBP-rP2. These two proteins are known to be involved in inhibition of mammary epithelial cell replication. Northern blot analysis showed that NaB treatment at 1-10 mM concentrations caused a dose-dependent stimulation of IGFBP-3 mRNA expression in cancerous cells and IGFBP-rP2 mRNA expression in both cancerous and non-cancerous cells. Protein data from Western ligand blot and immunoblot analyses demonstrated parallel results.In summary, we have demonstrated that NaB (i) uniformly suppresses DNA synthesis in both cancerous and non-cancerous mammary cells, and (ii) upregulates IGFBP-3 and IGFBP-rP2 mRNA and protein levels in cancerous and non-cancerous mammary cells. These results provide the first demonstration that butyrate regulates the IGFBP system in the human mammary system.

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“…Such compounds are for example butyrates, members of the group of histone deacetylase inhibitors (HDACs) (Gleave et al, 1998). Butyrates are naturally occurring short-chain fatty acids leading to differentiation of numerous cell types (Chen and Breitman, 1994).…”

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

et al. 2004

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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.

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Butyrate analogue, isobutyramide, inhibits tumor growth and time to androgen‐independent progression in the human prostate LNCaP tumor model

Cited by 14 publications

References 20 publications

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)

Effects of sodium butyrate on expression of members of the IGF-binding protein superfamily in human mammary epithelial cells

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

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