cancer is the overexpression of the ERG transcription factor due to gene rearrangement. 16–18 ERG is one of a number of potentially oncogenic transcription factors belonging to the ETS family, and 40–50% of prostate cancers possess an ERG gene fusion. Moreover, the ERG rearrangement appears to be associated with a more aggressive Raloxifene molecular weight form of prostate cancer and has been proposed as a prognostic factor for disease relapse.16,19–21 Since the VCAP prostate Fludarabine price cancer cell line has been reported to possess an ERG rearrangement fusion and elevated levels of ERG mRNA,18 we examined the effect of belinostat on ERG expression in this cell line and found that belinostat, even when used at a relatively low concentration for just 24 hr, strongly decreased the expression of this protein .
ERG expression was not observed in other prostate cell lines examined , consistent with the absence of the ERG fusion or ERG overexpression Dorzolamide ic50 in those cell lines.18 In contrast to its effects on ERG, belinostat increased the expression of the cell cycle inhibitory protein p21 in VCAP cells . The induction of p21 by HDACi, including belinostat3 has previously been described, and was included here mainly as a control to demonstrate that while some proteins are decreased following exposure of potently inhibited the growth of prostate cancer cell lines in vitro. Cell cycle analysis showed that belinostat induced a large increase in the proportion of cells in G2/M, consistent with drug induced growth arrest in this phase of the cell cycle.
In addition, belinostat was also cytotoxic to prostate cancer cell lines in vitro, as evidenced by a reduction in the number of viable cells to below starting cell numbers following exposure to belinostat and cell cycle data showing that belinostat exposure increased the proportion of cells with subG1 DNA content. Microscopic examination of cells following Iniparib belinostat exposure also clearly indicated the cytotoxic nature of this compound on prostate cancer cell lines. Most prostate cancer cell lines showed significant cell death following exposure to belinostat for 1–3 days. Of the various prostate cancer cell lines analyzed in this study, PC 3 cells were the least sensitive to belinostat mediated cytotoxicity, although even this cell line was susceptible to belinostat mediated cytotoxicity These in vitro findings, together with data obtained from a biodistribution study of radiolabeled belinostat in rodents which indicated the potential preference of this drug to localize to the prostate gland compared to most other tissues , prompted us to examine the activity of belinostat in a prostate cancer orthotopic xenograft model.
We chose to use PC 3 cells for this model even though this cell line is somewhat less sensitive to belinostatmediated cytotoxicity than other prostate cancer cell lines since the conditions for the orthotopic model had been previously established using this cell line. In previous physiotherapy investigations, belinostat was administered once/day in animal efficacy models.3–6 However, the in vitro exposure/washout data obtained on this compound prompted us to investigate more frequent dosing schedules in the present investigation with the goal of maintaining biologically active levels of belinostat over an extended period of time.
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