HA14-1 is a small molecule which has the potential of inducing apoptosis in cancerous cells. HA14-1 manifests an antagonistic effect on antiapoptotic protein Bcl-2 and consequently induces cell death in various cancerous cell lines. HA-14-1 also has the ability to inhibit ceramide glucosyltransferase. The IC50 value of HA14-1 against ceramide glucosyltransferase is 4.5μM, which is lower than that reported for Bcl-2 in vitro. Kinetic analyses revealed that HA14-1 is a competitive and mixed-type inhibitor with respect to C6-NBD-ceramide and UDP-glucose, respectively.P53 pathway to be the probable mechanism of action for the induction of apoptosis in HeLa cell by downregulating the effect of anti-apoptotic proteins suggesting that HA14-1 may provide therapeutic potential for the treatment of human cervical cancer.
|Cell lines||HF1A3, HF4.9 and HF28RA cells|
|Preparation method||Determining the cytotoxic effects of HA14-1 against different FL cell lines by the MTT assay. Briefly, incubating the cells (5000/well) in triplicate in 96-well plate in the presence or absence of HA14-1 for 20 h at 37 °C. Thereafter, adding the MTT solution to each well. After 4 h incubation at 37 °C, measuring the optical density (OD) by means of 96-well plate reader, with the extraction buffer as a blank. The following formula is used: percentage cell viability = (OD of the experiment samples/OD of the control) ?100. Sigmoidal dose-response curves are fitted to the mean cell viability plotted against log HA14-1 dose and lethal concentration 50% (LC50) values are calculated from the resulting curves using Prism 4.0 softw|
|Incubation time||20 h|
|Animal models||Female Swiss nude mice bearing BeGBM xenografts|
|Formulation||Free RPMI 1640-50% DMSO.|
|Administration||Inject at the site of cell injection.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Effect of HA14-1 on apoptosis-regulating proteins in HeLa cells.
Rehman K, et al. Chem Biol Drug Des. 2014 Mar;83(3):317-23. PMID: 24118733.
Regulation of HA14-1 mediated oxidative stress, toxic response, and autophagy by curcumin to enhance apoptotic activity in human embryonic kidney cells.
Ranjan K, et al. Biofactors. 2014 Jan-Feb;40(1):157-69. PMID: 23559532.
A small molecule inhibitor of Bcl-2, HA14-1, also inhibits ceramide glucosyltransferase.
Niino S, et al. Biochem Biophys Res Commun. 2013 Apr 5;433(2):170-4. PMID: 23485465.
The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells.
Nyhan MJ, et al. Br J Cancer. 2012 Feb 14;106(4):711-8. PMID: 22240779.
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