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


CONCLUSIONS
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.
Bredholt
Therese
T
The Gade Institute, University of Bergen, Bergen, Norway.
Dimba
Elizabeth Ao
EA
Hagland
Hanne R
HR
Wergeland
Line
L
Skavland
Jørn
J
Fossan
Kjell O
KO
Tronstad
Karl J
KJ
Johannessen
Anne C
AC
Vintermyr
Olav K
OK
Gjertsen
Bjørn T
BT
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D029754:Catha / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010641:Phenotype; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; D002166:Camptothecin