کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2598698 | 1133148 | 2015 | 8 صفحه PDF | دانلود رایگان |
• In vitro maximal tolerable dose (MTD) of Apicidin is exposure and time dependent in pancreatic carcinoma cells.
• The MTD is estimated to 100 nM for long term treatment and to at least 5000 nM for treatment not greater than 6 h.
• Apicidin is an attractive agent for interfering with the deacetylation process for potential pancreatic cancer intervention.
Apicidin is a potent histone deacetylase inhibitor (HDACI) that selectively binds to histone deacetylases (HDACs) class I and interferes with the deacetylation process, which results in modification of acetylation level of cellular proteins. The aim of the study was to investigate the potential time and dose dependent cytotoxicity of the test compound, Apicidin, in pancreatic cancer cells Capan-1 and Panc-1 as well as estimate maximal tolerable dose (MTD) of the test agent and determine EC50 using four complementary colorimetric cytotoxicity or viability assays. The cells were treated with increasing concentrations of Apicidin (0–5000 nM) for 2, 4 and 6 h (short term exposure) or 24, 48 and 72 h (long term exposure) before conducting cytotoxic analyses with lactate dehydrogenase assay or viability analyses with sulforhodamine B (SRB), methyl tetrazolium (MTT) and crystal violet (CV) assays. In order to investigate whether Apicidin irreversibly affects the cells already during the short term exposure, the medium containing Apicidin was removed and replaced with fresh culturing medium after 6 h of treatment. The cells were then incubated for additional 24, 48 or 72 h before carrying out the analysis. The results obtained from cytotoxicity and viability assays indicated, that Apicidin was well tolerated by both cell lines at concentrations below 100 nM at any given time point and at all applied concentrations during the short term (6 h or less) treatment. Continuous prolonged term exposures (48 h or greater) of the cells to Apicidin with concentration exceeding 100 nM resulted in significantly increasing cytotoxicity and sustained significant loss of cell viability. Moreover, long term exposure of pancreatic cancer cells Capan-1 and Panc-1 to Apicidin concentrations exceeding 100 nM showed an initial anti-proliferative effect before cytotoxicity onset. In summary, MTD was exposure time dependent and estimated to 100 nM for long term treatment and to at least 5000 nM for treatment not greater than 6 h. EC50 concentration of Apicidin was established after long term treatment, however with some variation when comparing the different assays and cell lines. Results from this study may encourage reinvestigating the capacity of potent HDACI Apicidin as an attractive agent for interfering with the deacetylation process catalyzed by HDACs for potential pancreatic cancer intervention.
Journal: Toxicology Letters - Volume 236, Issue 1, 2 July 2015, Pages 8–15