Abstract
Khat (Catha edulis (Vahl) Endl.) is an evergreen flowering shrub used as a stimulant in many regions worldwide including East Africa, the Arabian Peninsula, Europe, and the United States. Chewing leaves of khat induces excitement and euphoria, which are primarily attributed to two major constituents, cathinone and cathine. Khat also contains other important constituents such as cathedulins. A considerable number of studies reported side effects induced by the khat extracts to both embryos and adults. These include teratogenicity and developmental retardation, oral cancer and ulcers, high blood pressure, and myocardial infarction. So far, little attention has been paid to the effects of khat extracts on the molecular signaling interactions. We aimed in this study to investigate this through evaluating the effects of khat extracts on SKOV3, a human ovarian adenocarcinoma cell line. We show, by in vitro assays, that khat induces several cellular defects including reduced cell size, cell membrane damage, and apoptosis. At high khat extract concentrations, the cell metabolic activity, cell cycle, and cellular proliferation were affected. RT-qPCR analysis showed an increase in the gene expression of the apoptotic marker BAX, the tumor suppressor p53, and the inflammatory cytokine IL-6. Protein expression analysis by immunostaining showed downregulation of β-catenin, E-cadherin, and Ki-67 and upregulation of FZD8 and SPRY2, suggesting that Wnt and FGF signaling were implicated. SwissTargetPrediction in silico analysis showed that khat constituents cathine, cathinone, catheduline K2, and catheduline E5 bind to family A G-protein-coupled receptor, cause many neurological diseases and disorders such as Alzheimer's, schizophrenia, depression, and anxiety, and induce many ovarian cancer-related diseases. The analysis also showed that important signaling pathways such as CREB, Wnt, FGF, IL-6, and ERK/MAPK, and that of the endometrial cancer, and cell cycle were implicated. Upstream regulators of cathine and cathinone were found to potentially target several molecules including interleukin-8, MMP2, PLAU, and micro-RNAs. In conclusion, khat induces significant cellular and molecular changes that could potentially cause a wide range of serious diseases and syndromes. Such an impact could have a heavy burden on the health care system in the countries where khat is consumed.
Highlights
Khat (Catha edulis (Vahl) Endl.) is an evergreen shrub grown in the Horn of Africa and the Arab Peninsula (Al-Qirim et al, 2002; Wabe, 2011)
Treatment with different concentrations (10, 30, 100, and 300 μg/ml; 1, 3, and 10 mg/ml) of khat extracts for 24–72 h showed variable inhibition of SKOV3 cell growth and proliferation compared to the control (Figure 1)
Following treatment with different concentrations (10, 30, 100, and 300 μg/ml; 1, 3, and 10 mg/ml) of khat extracts for 24–72 h, a mild to moderate decline in the metabolic activity of the SKOV3 cells was observed with most concentrations compared to the control (Figure 2)
Summary
Khat (Catha edulis (Vahl) Endl.) is an evergreen shrub grown in the Horn of Africa and the Arab Peninsula (Al-Qirim et al, 2002; Wabe, 2011). Khat leaves contain a considerable number of alkaloids, among which major active constituents are cathinone (S-(-)-2-amino-1-phenyl-1propanone), cathine (1S, 2S-norpseudoephedrine), 62 highly complex cathedulins (polyhydroxylated sesquiterpenes), flavonoids, glycosides, ascorbic acid, tannins, sterols, triterpenes, and smaller amounts of 1R, 2S-norephedrine (Halbach, 1972; Kalix and Braenden, 1985; Kite et al, 2003; Wabe, 2011; Alsanosy et al, 2020; Kiros, 2020). Young and mature khat leaves constituent analysis has been recently welldocumented. This hierarchical cluster analysis showed that cathine and cathinone were the major components and associated with significant cytotoxicity (Alsanosy et al, 2020). The use of khat for medicinal treatment is not yet fully understood, but it has been used to treat serious diseases such as gonorrhea, asthma, chest complications, depression, gastric ulcers, obesity, and tiredness (reviewed by Kiros, 2020)
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