Estudio del efecto pro-apoptótico de los diterpenos derivados del labdano en células tumorales

Resumen

Labdane diterpenoids have a broad spectrum of biological activities including antibacterial, antiviral, and anti¿inflammatory properties. However, little is known about their possible role in the apoptotic cell death machinery. Here, we report that labdane diterpenoids induce apoptosis in different tumor cell lines by activating caspasa¿8 in the extrinsic death receptor pathway, with subsequent participation of mitochondrial signaling. Activation of caspasa¿8 by diterpenoids was followed by a decrease in mitochondrial membrane potential, the release of apoptotic factors from mitochondria to the cytosol, and subsequent activation of caspasas¿9 and ¿3. Diterpenoids also led to time¿dependent cleavage of Bid. Inhibition of caspase¿8 abrogated these processes, suggesting that the death receptor pathway plays a critical role in the apoptotic events induced by labdane diterpenoids. In addition, pretreating cells with neutralizing antibodies to Fas ligand, tumor necrosis factor receptor 1 (TNF¿R1) and tumor necrosis factor related apoptosis inducing ligand receptor 2 (TRAIL¿R2) inhibited diterpenoid¿induced apoptosis, revealing it to be dependent on these death receptors. Diterpenoid treatment also induced a significant increase in the generation of reactive oxygen species (ROS). However, increased ROS production was not directly involved in diterpenoid¿triggered apoptosis. On the other hand, treatment with diterpenoids make tumor cells more sensitive against TRAIL¿inducing apoptosis. Taken together, these results indicate that the labdane diterpenoids can induce apoptosis through activation of the death receptor pathway and in turn sensitize cancer cells to TRAIL, what characterizes these natural compounds as novel potential antitumor agents for use in both monotherapy or combination therapy with different drugs.