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Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells

Abstract

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.

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Abbreviations

AIF:

apoptosis-inducing factor

BetA:

betulinic acid

FACS:

fluorescence-activated cell sorting

FADD:

Fas-associated death domain

IAPs:

inhibitor of apoptosis proteins

Smac:

second mitochondria-derived activator of caspase

TNF:

tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

XIAP:

X-linked inhibitor of apoptosis

zVAD.fmk:

benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

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Acknowledgements

We thank PH Krammer (Heidelberg, Germany) for anti-caspase-8 antibody and Petra Miller-Rostek for expert technical assistance. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie, the Ministry of Science, Research and Arts of Baden-Württemberg, IZKF Ulm, Wilhelm-Sander-Stiftung, Else-Kröner-Stiftung, the Deutsche Kinderkrebsstiftung and the European community (to KMD and S F).

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Correspondence to Simone Fulda.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Fulda, S., Jeremias, I. & Debatin, KM. Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 23, 7611–7620 (2004). https://doi.org/10.1038/sj.onc.1207970

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