Research

Camptothecin and khat (Catha edulis Forsk.) induced distinct cell death phenotypes involving modulation of c-FLIP_L, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines

Therese Bredholt^1,4 , Elizabeth AO Dimba² , Hanne R Hagland³ , Line Wergeland⁴ , Jørn Skavland⁴ , Kjell O Fossan⁵ , Karl J Tronstad³ , Anne C Johannessen^1,6 , Olav K Vintermyr⁶ and Bjørn T Gjertsen^4,7

¹  The Gade Institute, University of Bergen, Bergen, Norway

²  Department of Oral and Maxillofacial Surgery, University of Nairobi, Nairobi, Kenya

³  Department of Biomedicine, University of Bergen, Bergen, Norway

⁴  Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway

⁵  Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway

⁶  Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway

⁷  Department of Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

author email corresponding author email

Molecular Cancer 2009, 8:101doi:10.1186/1476-4598-8-101

Published:	13 November 2009

Abstract

Background

An organic extract of the recreational herb khat (Catha edulis Forsk.) triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity.

Results

Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIP_L cleavage and procaspase-8 activation.

Conclusion

Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.