Critical role of the death receptor pathway in the antitumoral effects induced by hispanolone derivatives.
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 hispanolone derivatives, a group of labdane diterpenoids, induce apoptosis in different tumor cell lines by activating caspase-8 with subsequent participation of mitochondrial signaling. Activation of caspase-8 by hispanolone derivatives was followed by a decrease in mitochondrial membrane potential, the release of apoptotic factors from mitochondria to the cytosol, and activation of caspases-9 and 3. Hispanolone derivatives also led to a time-dependent cleavage of Bid. Inhibition of caspase-8 abrogated these processes, suggesting that the death receptor pathway has a critical role in the apoptotic events induced by hispanolone derivatives. In addition, silencing death receptors with small interfering RNA s or pretreating cells with neutralizing antibodies to Fas ligand, tumor necrosis factor receptor 1 (TNF-R1), and TNF-α receptor 2 (TRAIL) inhibited diterpenoid-induced apoptosis, revealing it to be dependent on these death receptors. Interestingly, hispanolone derivatives had no effect on non-tumor cells. Consistently, in vivo bioluminescence imaging corroborates this antineoplasic effect, as hispanolone derivatives significantly decrease cancer growth in tumor xenograft assays. These data demostrate the antitumoral effects of hispanolone derivatives and provide relevant preclinical validation for the use of these compounds as potent therapeutic agents in cancer treatment.
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
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D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria; D034622:RNA Interference; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism
D057134:Antibodies, Neutralizing; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053199:TNF Receptor-Associated Death Domain Protein; C505640:Tnfrsf10b protein, mouse; C481226:Tradd protein, mouse; C501367:hispanolone; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9