66 Synthesis and Induction of Apoptosis Signaling Pathway of Ent-Kaurene Derivatives

Wednesday, November 4, 2009
Ballroom A+B (Camino Real Hotel)
Idaira Hueso Falcón , Instituto Universitario de Bio-Orgánica "Antonio González", Universidad de La Laguna, La Laguna, Tenerife, Spain
Natalia Girón , Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
Juan M. Amaro-Luis , Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
Beatriz de las Heras , Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain
Sonsoles Hortelano , Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
A. Estévez-Braun , Instituto Universitario de Bio-Orgánica "Antonio González", Universidad de La Laguna, La Laguna, Tenerife, Spain
Thirty one ent-kaurene derivatives were prepared from kaurenoic acid, grandiflorenic acid, 15α-acetoxy kaurenoic acid and 16α-hydroxy kaurenoic acid. They were tested for their ability to inhibit cell growth in the Mouse leukaemic macrophagic RAW 264.7 cell line. The most effective compounds were 12, 20, 21 and 23. Similar effects were obtained in other human cancer cell lines such as Hela, HepG2 and HT-29, although RAW 264.7 cells were more sensitive.
The apoptotic potential of the most active compounds was investigated and they were able to induce apoptosis being compound 12 the best inducer. The caspase-3, -8 and -9 activities were measured. The results obtained showed that compounds 12, 21 and 23 induce apoptosis via the activation of caspase-8, whereas compound 20 induces apoptosis via caspase-9.
Inmunoblot analysis of the expression of p53, Bax, Bcl-2, Bcl-x1 and IAPs in RAW 264.7 cells was also carried out. When cells were exposed to 5 μM of the different compounds, expression levels of p53 and Bax increased whereas levels of antiapoptotic proteins such as Bcl-2, Bcl-x1 and IAPs decreased.

In conclusion, kaurene derivatives (12, 20, 21 and 23) induce apoptosis via both the mitochondrial and membrane death receptor pathways, involving the Bcl-2 family proteins. Taken together these results provide a role of kaurene derivatives as apoptotic inducers in tumor cells and suggest their potential application as antitumor agents.

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