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Cytotoxic indole alkaloids against human leukemia cell lines from the toxic plant Peganum harmala.

Wang C, Zhang Z, Wang Y, He X - Toxins (Basel) (2015)

Bottom Line: The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity.Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L.The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. wangchunhua@whu.edu.cn.

ABSTRACT
Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

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Related in: MedlinePlus

Apoptosis via Ras/Raf/ERK signaling pathway in U-937 cells after HMC treatment. (A) Cell viability was assessed using MTT method in U-937 cells after pretreated by 10 µmol/L Genistein for 1 h, and then the cells were incubated without or with 2.0 µmol/L HMC for 48 h. (B,C) Expressions of Ras, p-Raf and P-ERK1/2 were detected using Western blot analysis and the quantity results were showed in Figure 3C. Data are presented as means ± SEM of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.
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toxins-07-04507-f003: Apoptosis via Ras/Raf/ERK signaling pathway in U-937 cells after HMC treatment. (A) Cell viability was assessed using MTT method in U-937 cells after pretreated by 10 µmol/L Genistein for 1 h, and then the cells were incubated without or with 2.0 µmol/L HMC for 48 h. (B,C) Expressions of Ras, p-Raf and P-ERK1/2 were detected using Western blot analysis and the quantity results were showed in Figure 3C. Data are presented as means ± SEM of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.

Mentions: Unusual activation of Ras/Raf/MAPK signaling pathway is one of main characteristic of human cancer. In this study, the Ras/Raf/MAPK pathway was investigated in HMC-induced U-937 cell apoptosis. Genistein, a broad-spectrum inhibitor of protein tyrosine kinases (PTKs), was used to detect the cell viability after HMC treatment. As expected, genistein could significantly decrease the cell viability after HMC co-incubation compared with HMC-treated only (Figure 3A). Moreover, the expressions of Ras/Raf/ERK in U-937 cells were detected after HMC treatment in different time courses. The results strongly suggested that HMC could down-regulate the expressions of Ras, p-Raf and p-ERK1/2 (Figure 3B,C), while the total ERK kept no change.


Cytotoxic indole alkaloids against human leukemia cell lines from the toxic plant Peganum harmala.

Wang C, Zhang Z, Wang Y, He X - Toxins (Basel) (2015)

Apoptosis via Ras/Raf/ERK signaling pathway in U-937 cells after HMC treatment. (A) Cell viability was assessed using MTT method in U-937 cells after pretreated by 10 µmol/L Genistein for 1 h, and then the cells were incubated without or with 2.0 µmol/L HMC for 48 h. (B,C) Expressions of Ras, p-Raf and P-ERK1/2 were detected using Western blot analysis and the quantity results were showed in Figure 3C. Data are presented as means ± SEM of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663518&req=5

toxins-07-04507-f003: Apoptosis via Ras/Raf/ERK signaling pathway in U-937 cells after HMC treatment. (A) Cell viability was assessed using MTT method in U-937 cells after pretreated by 10 µmol/L Genistein for 1 h, and then the cells were incubated without or with 2.0 µmol/L HMC for 48 h. (B,C) Expressions of Ras, p-Raf and P-ERK1/2 were detected using Western blot analysis and the quantity results were showed in Figure 3C. Data are presented as means ± SEM of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.
Mentions: Unusual activation of Ras/Raf/MAPK signaling pathway is one of main characteristic of human cancer. In this study, the Ras/Raf/MAPK pathway was investigated in HMC-induced U-937 cell apoptosis. Genistein, a broad-spectrum inhibitor of protein tyrosine kinases (PTKs), was used to detect the cell viability after HMC treatment. As expected, genistein could significantly decrease the cell viability after HMC co-incubation compared with HMC-treated only (Figure 3A). Moreover, the expressions of Ras/Raf/ERK in U-937 cells were detected after HMC treatment in different time courses. The results strongly suggested that HMC could down-regulate the expressions of Ras, p-Raf and p-ERK1/2 (Figure 3B,C), while the total ERK kept no change.

Bottom Line: The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity.Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L.The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. wangchunhua@whu.edu.cn.

ABSTRACT
Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

Show MeSH
Related in: MedlinePlus