Early loss of mitochondrial inner transmembrane potential in khat-induced cell death of primary normal human oral cells

Lukandu, Ochiba M.; Bredholt, Therese; Neppelberg, Evelyn; Gjertsen, Bjørn Tore; Johannessen, Anne Christine; Vintermyr, Olav Karsten; Costea, Daniela Elena

doi:10.1016/j.tox.2009.06.024

Cited by 16 publications

(17 citation statements)

References 28 publications

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“…We previously reported that khat induced ROS in normal oral keratinocytes and fibroblasts in vitro [2] and recently that khat affected mitochondrial inner transmembrane potential in these primary cells [32]. Another study suggests that khat and the alkaloid fraction produce oxidative stress in rats by reducing the levels of free radical scavenging enzymes and glucose, leading to increased ROS and toxicity [33].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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BackgroundAn 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.ResultsKhat 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.ConclusionKhat 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…34 A study showed that Qat induced alterations such as premature differentiation, senescence and abnormal keratinization, which was accompanied by increased levels of p38. 35 Other studies have also found Qat to be associated with free radical production.…”

Section: Qat Use and Effects On Healthmentioning

confidence: 99%

Qat Chewing and Risk of Potentially Malignant and Malignant Oral Disorders: A Systematic Review

El‐Zaemey

Schüz

Léon

2015

Int J Occup Environ Med

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“…Previous studies suggest that CsA can modulate mitochondrial membrane permeability to prevent cytochrome c release from mitochondria, while concomitantly inducing the cellular apoptosis that accompanies nephrotoxicity. However, others observed that CsA‐dependent attenuation of the mitochondrial membrane permeability transition could protect oral epithelial cells from apoptosis. Moreover, CsA can also impact protein synthesis .…”

Section: Resultsmentioning

confidence: 99%

“…CsA attenuates the mitochondria membrane permeability transition and prevents cytochrome c release from mitochondria [9,17,18]. This blocks a caspase-dependent apoptotic signalling pathway [9,19,20] and consequently retards the anagen-to-catagen transition in hair follicles [15,21,22].…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A increases hair follicle growth by suppressing apoptosis‐inducing factor nuclear translocation: a new mechanism

Lan

Liu

Zhao

et al. 2015

Fundamemntal Clinical Pharma

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Cyclosporine A (CsA) enhances hair growth through caspase-dependent pathways by retarding anagen-to-catagen phase transition in the hair follicle growth cycle. Whether apoptosis-inducing factor (AIF), a protein that induces caspase-independent apoptosis, can regulate the hair follicle cycle in response to CsA is currently unclear. Here, we show that the pro-hair growth properties of CsA are in part due to blockage of AIF nuclear translocation. We first isolate hair follicles from murine dorsal skin. We then used Western blot, immunohistochemistry and immunofluorescence to evaluate the expression and localization of AIF in hair follicles. We also determined whether modulation of AIF was responsible for the effects of CsA at the anagen-to-catagen transition. AIF was expressed in hair follicles during the anagen, catagen and telogen phases. There was significant nuclear translocation of AIF as hair follicles transitioned from anagen to late catagen phase; this was inhibited by CsA, likely due to reduced cyclophilin A expression and attenuated AIF release from mitochondria. However, we note that AIF translocation was not completely eliminated, which likely explains why the transition to catagen phase was severely retarded by CsA, rather than being completely inhibited. We speculate that blockade of the AIF signalling pathway is a critical event required for CsA-dependent promotion of hair growth in mice. The study of AIF-related signalling pathways may provide insight into hair diseases and suggest potential novel therapeutic strategies.

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Early loss of mitochondrial inner transmembrane potential in khat-induced cell death of primary normal human oral cells

Cited by 16 publications

References 28 publications

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

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

Qat Chewing and Risk of Potentially Malignant and Malignant Oral Disorders: A Systematic Review

Cyclosporine A increases hair follicle growth by suppressing apoptosis‐inducing factor nuclear translocation: a new mechanism

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