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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

HMC initiated apoptosis in U-937 cells through mitochondrial and Caspase cascade. (A) Apoptotic U-937 cells were observed after the cells were stained by Hoechst 33258. (B) Mitochondrial transmembrane potential was reduced in U-937 cells stained by Rodamine123. (C) The ATP level was also reduced in U-937 cells. (D–F) HMC impacted the mRNA levels and protein expressions of Bax and Bcl-2 in U-937 cells leading to the activation of caspase 3. Data are presented as means ± SD of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.
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toxins-07-04507-f002: HMC initiated apoptosis in U-937 cells through mitochondrial and Caspase cascade. (A) Apoptotic U-937 cells were observed after the cells were stained by Hoechst 33258. (B) Mitochondrial transmembrane potential was reduced in U-937 cells stained by Rodamine123. (C) The ATP level was also reduced in U-937 cells. (D–F) HMC impacted the mRNA levels and protein expressions of Bax and Bcl-2 in U-937 cells leading to the activation of caspase 3. Data are presented as means ± SD of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.

Mentions: Based on the cytotoxic results, compound 8 (HMC) has pronounced cytotoxicity against human leukemia cells, especially to U-937 cells. Therefore, it was worthy of investigating the cytotoxic mechanism of HMC in U-937 cell death. To elucidate the characteristics of HMC-induced U-937 cells, morphologic changes were examined. Interestingly, when the U-937 cells were exposed to 2.0 μmol/L HMC for 24 h and stained by Hoechst 33258, the characteristic morphologic alterations of cell apoptosis were observed, including membrane blebbing, nuclear condensation and granular apoptotic bodies (Figure 2A).


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)

HMC initiated apoptosis in U-937 cells through mitochondrial and Caspase cascade. (A) Apoptotic U-937 cells were observed after the cells were stained by Hoechst 33258. (B) Mitochondrial transmembrane potential was reduced in U-937 cells stained by Rodamine123. (C) The ATP level was also reduced in U-937 cells. (D–F) HMC impacted the mRNA levels and protein expressions of Bax and Bcl-2 in U-937 cells leading to the activation of caspase 3. Data are presented as means ± SD 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-f002: HMC initiated apoptosis in U-937 cells through mitochondrial and Caspase cascade. (A) Apoptotic U-937 cells were observed after the cells were stained by Hoechst 33258. (B) Mitochondrial transmembrane potential was reduced in U-937 cells stained by Rodamine123. (C) The ATP level was also reduced in U-937 cells. (D–F) HMC impacted the mRNA levels and protein expressions of Bax and Bcl-2 in U-937 cells leading to the activation of caspase 3. Data are presented as means ± SD of three independent tests. *p < 0.05 versus control, **p < 0.01 versus control.
Mentions: Based on the cytotoxic results, compound 8 (HMC) has pronounced cytotoxicity against human leukemia cells, especially to U-937 cells. Therefore, it was worthy of investigating the cytotoxic mechanism of HMC in U-937 cell death. To elucidate the characteristics of HMC-induced U-937 cells, morphologic changes were examined. Interestingly, when the U-937 cells were exposed to 2.0 μmol/L HMC for 24 h and stained by Hoechst 33258, the characteristic morphologic alterations of cell apoptosis were observed, including membrane blebbing, nuclear condensation and granular apoptotic bodies (Figure 2A).

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