Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells.
We previously reported that the TRAIL (tumor necrosis factor (TNF)-related apoptosis-inducing ligand)-induced death signal requires amplification by mitochondria in certain cell types, for example, in type II cells. Here, we provide for the first time evidence that the natural compound betulinic acid (BetA) cooperated with TRAIL to induce apoptosis in tumor cells. Through functional complementation, simultaneous stimulation of the death receptor pathway by TRAIL and the mitochondrial pathway by BetA resulted in complete activation of effector caspases, apoptosis and inhibition of clonogenic survival. BetA and TRAIL cooperated to trigger loss of mitochondrial membrane potential and release of cytochrome c and Smac from mitochondria. Also, combination treatment with BetA and TRAIL resulted in increased cleavage of caspase-8 and Bid indicating that activation of effector caspases may feed back in a positive amplification loop. Importantly, the combination treatment with BetA and TRAIL cooperated to induce apoptosis in different tumor cell lines and also in primary tumor cells, but not in normal human fibroblasts indicating some tumor specificity. Since most human cancers represent type II cells, triggering the mitochondrial pathway by BetA may be a novel approach to enhance the efficacy of TRAIL-based therapies, which warrants further investigation.
Fulda
Simone
S
University Children's Hospital, Prittwitzstr. 43, D-89075 Ulm, Germany. simone.fulda@medizin.uni-ulm.de
Jeremias
Irmela
I
Debatin
Klaus-Michael
KM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D007680:Kidney Neoplasms; D008527:Medulloblastoma; D008545:Melanoma; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D009447:Neuroblastoma; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D000094062:Betulinic Acid
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D000094062:Betulinic Acid