Limits...
Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model.

Nagy LI, Molnár E, Kanizsai I, Madácsi R, Ózsvári B, Fehér LZ, Fábián G, Marton A, Vizler C, Ayaydin F, Kitajka K, Hackler L, Mátés L, Deák F, Kiss I, Puskás LG - Lipids Health Dis (2013)

Bottom Line: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010.The analogs mainly accumulated in the liver.These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.

View Article: PubMed Central - HTML - PubMed

Affiliation: AVIDIN Ltd,, Szeged, Hungary. puskas.szbk@gmail.com.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options.

Results: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size.

Conclusion: These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.

Show MeSH

Related in: MedlinePlus

Chemical structure of trifluoro-amino-phthalimides: Ac-915 and Ac-2010 and their EC50 values in different liver cancer cell lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4222488&req=5

Figure 1: Chemical structure of trifluoro-amino-phthalimides: Ac-915 and Ac-2010 and their EC50 values in different liver cancer cell lines.

Mentions: Two novel amino-trifluoro-phtalimide analogs synthesized by Avidin Ltd. Ac-915 (2-[2,6-bis(propane-2-yl)phenyl]-4-{[(3R)-1,1-dioxo-2,3-dihydro-thiophene-3-yl]amino}-5,6,7-trifluoro-2,3-dihydro-1H-isoindole-1,3-dione) and Ac-2010 (2-[2,6-bis(propane-2-yl)phenyl]- 5,6,7-trifluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}-3-(2-chloroacetyl)urea) showed superior cytotoxic activity in cancer cells and therefore were selected to the present study. Their cytotoxic effects on human hepatocellular carcinoma cell lines (namely: HepG2, Hep3B and Huh7) were measured by using the MTS assay. EC50 values for 48 h exposure were summarized next to their chemical structures in Figure 1. Both Ac-915 and Ac-2010 induced cell death of liver cancer cells at sub- or low micromolar ranges.


Lipid droplet binding thalidomide analogs activate endoplasmic reticulum stress and suppress hepatocellular carcinoma in a chemically induced transgenic mouse model.

Nagy LI, Molnár E, Kanizsai I, Madácsi R, Ózsvári B, Fehér LZ, Fábián G, Marton A, Vizler C, Ayaydin F, Kitajka K, Hackler L, Mátés L, Deák F, Kiss I, Puskás LG - Lipids Health Dis (2013)

Chemical structure of trifluoro-amino-phthalimides: Ac-915 and Ac-2010 and their EC50 values in different liver cancer cell lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4222488&req=5

Figure 1: Chemical structure of trifluoro-amino-phthalimides: Ac-915 and Ac-2010 and their EC50 values in different liver cancer cell lines.
Mentions: Two novel amino-trifluoro-phtalimide analogs synthesized by Avidin Ltd. Ac-915 (2-[2,6-bis(propane-2-yl)phenyl]-4-{[(3R)-1,1-dioxo-2,3-dihydro-thiophene-3-yl]amino}-5,6,7-trifluoro-2,3-dihydro-1H-isoindole-1,3-dione) and Ac-2010 (2-[2,6-bis(propane-2-yl)phenyl]- 5,6,7-trifluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}-3-(2-chloroacetyl)urea) showed superior cytotoxic activity in cancer cells and therefore were selected to the present study. Their cytotoxic effects on human hepatocellular carcinoma cell lines (namely: HepG2, Hep3B and Huh7) were measured by using the MTS assay. EC50 values for 48 h exposure were summarized next to their chemical structures in Figure 1. Both Ac-915 and Ac-2010 induced cell death of liver cancer cells at sub- or low micromolar ranges.

Bottom Line: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010.The analogs mainly accumulated in the liver.These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.

View Article: PubMed Central - HTML - PubMed

Affiliation: AVIDIN Ltd,, Szeged, Hungary. puskas.szbk@gmail.com.

ABSTRACT

Background: Hepatocellular carcinoma (HCC) is the most frequent and aggressive primary tumor of the liver and it has limited treatment options.

Results: In this study, we report the in vitro and in vivo effects of two novel amino-trifluoro-phtalimide analogs, Ac-915 and Ac-2010. Both compounds bind lipid droplets and endoplasmic reticulum membrane, and interact with several proteins with chaperone functions (HSP60, HSP70, HSP90, and protein disulfide isomerase) as determined by affinity chromatography and resonant waveguide optical biosensor technology. Both compounds inhibited protein disulfide isomerase activity and induced cell death of different HCC cells at sub or low micromolar ranges detected by classical biochemical end-point assay as well as with real-time label-free measurements. Besides cell proliferation inhibiton, analogs also inhibited cell migration even at 250 nM. Relative biodistribution of the analogs was analysed in native tissue sections of different organs after administration of drugs, and by using fluorescent confocal microscopy based on the inherent blue fluorescence of the compounds. The analogs mainly accumulated in the liver. The effects of Ac-915 and Ac-2010 were also demonstrated on the advanced stages of hepatocarcinogenesis in a transgenic mouse model of N-nitrosodiethylamine (DEN)-induced HCC. Significantly less tumor development was found in the livers of the Ac-915- or Ac-2010-treated groups compared with control mice, characterized by less liver tumor incidence, fewer tumors and smaller tumor size.

Conclusion: These results imply that these amino-trifluoro-phthalimide analogs could serve potent clinical candidates against HCC alone or in combination with dietary polyunsaturated fatty acids.

Show MeSH
Related in: MedlinePlus