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N-Farnesyloxy-norcantharimide inhibits progression of human leukemic Jurkat T cells through regulation of mitogen-activated protein kinase and interleukin-2 production.

Chang MC, Wu JY, Liao HF, Chen YJ, Kuo CD - Anticancer Drugs (2015)

Bottom Line: Thus, NOC15 is 1.36-fold (=11.14÷8.17) beneficial as an anticancer agent toward Jurkat T cells compared with NCTD.However, NOC15 exerted no effects on the Jun-N-terminal kinase 1/2 (JNK1/2) signaling pathway, the production of IL-8, and tumor necrosis factor-α.We conclude that the anticancer activity of the newly synthesized NOC15 is 1.36-fold beneficial than NCTD as an anticancer agent and that NOC15 can increase the percentage of cells in the sub-G1 phase through the stimulation of p38 and ERK1/2 of the MAPK signaling pathway and the inhibition of calcineurin expression and IL-2 production.

View Article: PubMed Central - PubMed

Affiliation: aLaboratory of Biophysics, Department of Medical Research, Taipei Veterans General Hospital bDepartment of Radiation Oncology, Mackay Memorial Hospital, Taipei cDepartment of Microbiology, Immunology and Biopharmaceutics, College of Life Sciences dDepartment of Molecular Biology and Biochemistry, National Chiayi University, Chiayi, Taiwan.

ABSTRACT
This study investigated the anticancer effects of N-farnesyloxy-norcantharimide (NOC15), a newly synthesized norcantharidin (NCTD) analogue, on human leukemic Jurkat T cells and the signaling pathway underlying its effects. We found that the half maximal inhibitory concentration (IC50) of NOC15 on Jurkat T cells is 1.4 μmol/l, which is 11.14-fold (=15.6÷1.4) smaller than the 15.6 μmol/l of NCTD on Jurkat T cells, whereas the IC50 of NOC15 on human normal lymphoblast (HNL) is 207.9 μmol/l, which is 8.17-fold (=1698.0÷207.8) smaller than the 1698.0 μmol/l of NCTD on HNL cells. These results indicated that NOC15 exerts a higher anticancer effect on Jurkat T cells and has higher toxicity toward HNL cells than NCTD. Thus, NOC15 is 1.36-fold (=11.14÷8.17) beneficial as an anticancer agent toward Jurkat T cells compared with NCTD. Moreover, NOC15 can increase the percentage of cells in the sub-G1 phase and reduce the cell viability of Jurkat T cells, stimulate p38 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) of mitogen-activated protein kinases (MAPKs) signaling pathway, and inhibit calcineurin expression and interleukin-2 (IL-2) production. However, NOC15 exerted no effects on the Jun-N-terminal kinase 1/2 (JNK1/2) signaling pathway, the production of IL-8, and tumor necrosis factor-α. We conclude that the anticancer activity of the newly synthesized NOC15 is 1.36-fold beneficial than NCTD as an anticancer agent and that NOC15 can increase the percentage of cells in the sub-G1 phase through the stimulation of p38 and ERK1/2 of the MAPK signaling pathway and the inhibition of calcineurin expression and IL-2 production. The NOC15 may have the potential of being developed into an anticancer agent in the future.

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Cell cycle variation of NOC15 on human Jurkat T cell. (a) Control; (b) NOC15 (24 h); (c) NOC15 (48 h); (d) percent of cells in each cell cycle phase. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then treated with NOC15 (IC50) for 24 or 48 h. The cells were collected, fixed, and stained with propidium iodide to determine the DNA contents using a flow cytometer. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. #P<0.05 versus NOC15 (24 h). NOC15 can increase the percentage of cells in the sub-G1 phase and the G2/M phase, but decrease the percentage of cells in the S phase. IC50, half maximal inhibitory concentration; ION, ionomycin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
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Figure 2: Cell cycle variation of NOC15 on human Jurkat T cell. (a) Control; (b) NOC15 (24 h); (c) NOC15 (48 h); (d) percent of cells in each cell cycle phase. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then treated with NOC15 (IC50) for 24 or 48 h. The cells were collected, fixed, and stained with propidium iodide to determine the DNA contents using a flow cytometer. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. #P<0.05 versus NOC15 (24 h). NOC15 can increase the percentage of cells in the sub-G1 phase and the G2/M phase, but decrease the percentage of cells in the S phase. IC50, half maximal inhibitory concentration; ION, ionomycin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.

Mentions: To examine the cell cycle variation of NOC15, the DNA histogram was determined with propidium iodide staining using flow cytometry. As shown in Fig. 2, NOC15 increased the percentage of cells in the sub-G1 phase and the G2/M phase, but decreased the percentage of cells in the S phase. This result indicates that NOC15 can inhibit cell growth by affecting the cell cycle.


N-Farnesyloxy-norcantharimide inhibits progression of human leukemic Jurkat T cells through regulation of mitogen-activated protein kinase and interleukin-2 production.

Chang MC, Wu JY, Liao HF, Chen YJ, Kuo CD - Anticancer Drugs (2015)

Cell cycle variation of NOC15 on human Jurkat T cell. (a) Control; (b) NOC15 (24 h); (c) NOC15 (48 h); (d) percent of cells in each cell cycle phase. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then treated with NOC15 (IC50) for 24 or 48 h. The cells were collected, fixed, and stained with propidium iodide to determine the DNA contents using a flow cytometer. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. #P<0.05 versus NOC15 (24 h). NOC15 can increase the percentage of cells in the sub-G1 phase and the G2/M phase, but decrease the percentage of cells in the S phase. IC50, half maximal inhibitory concentration; ION, ionomycin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4588604&req=5

Figure 2: Cell cycle variation of NOC15 on human Jurkat T cell. (a) Control; (b) NOC15 (24 h); (c) NOC15 (48 h); (d) percent of cells in each cell cycle phase. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then treated with NOC15 (IC50) for 24 or 48 h. The cells were collected, fixed, and stained with propidium iodide to determine the DNA contents using a flow cytometer. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. #P<0.05 versus NOC15 (24 h). NOC15 can increase the percentage of cells in the sub-G1 phase and the G2/M phase, but decrease the percentage of cells in the S phase. IC50, half maximal inhibitory concentration; ION, ionomycin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
Mentions: To examine the cell cycle variation of NOC15, the DNA histogram was determined with propidium iodide staining using flow cytometry. As shown in Fig. 2, NOC15 increased the percentage of cells in the sub-G1 phase and the G2/M phase, but decreased the percentage of cells in the S phase. This result indicates that NOC15 can inhibit cell growth by affecting the cell cycle.

Bottom Line: Thus, NOC15 is 1.36-fold (=11.14÷8.17) beneficial as an anticancer agent toward Jurkat T cells compared with NCTD.However, NOC15 exerted no effects on the Jun-N-terminal kinase 1/2 (JNK1/2) signaling pathway, the production of IL-8, and tumor necrosis factor-α.We conclude that the anticancer activity of the newly synthesized NOC15 is 1.36-fold beneficial than NCTD as an anticancer agent and that NOC15 can increase the percentage of cells in the sub-G1 phase through the stimulation of p38 and ERK1/2 of the MAPK signaling pathway and the inhibition of calcineurin expression and IL-2 production.

View Article: PubMed Central - PubMed

Affiliation: aLaboratory of Biophysics, Department of Medical Research, Taipei Veterans General Hospital bDepartment of Radiation Oncology, Mackay Memorial Hospital, Taipei cDepartment of Microbiology, Immunology and Biopharmaceutics, College of Life Sciences dDepartment of Molecular Biology and Biochemistry, National Chiayi University, Chiayi, Taiwan.

ABSTRACT
This study investigated the anticancer effects of N-farnesyloxy-norcantharimide (NOC15), a newly synthesized norcantharidin (NCTD) analogue, on human leukemic Jurkat T cells and the signaling pathway underlying its effects. We found that the half maximal inhibitory concentration (IC50) of NOC15 on Jurkat T cells is 1.4 μmol/l, which is 11.14-fold (=15.6÷1.4) smaller than the 15.6 μmol/l of NCTD on Jurkat T cells, whereas the IC50 of NOC15 on human normal lymphoblast (HNL) is 207.9 μmol/l, which is 8.17-fold (=1698.0÷207.8) smaller than the 1698.0 μmol/l of NCTD on HNL cells. These results indicated that NOC15 exerts a higher anticancer effect on Jurkat T cells and has higher toxicity toward HNL cells than NCTD. Thus, NOC15 is 1.36-fold (=11.14÷8.17) beneficial as an anticancer agent toward Jurkat T cells compared with NCTD. Moreover, NOC15 can increase the percentage of cells in the sub-G1 phase and reduce the cell viability of Jurkat T cells, stimulate p38 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) of mitogen-activated protein kinases (MAPKs) signaling pathway, and inhibit calcineurin expression and interleukin-2 (IL-2) production. However, NOC15 exerted no effects on the Jun-N-terminal kinase 1/2 (JNK1/2) signaling pathway, the production of IL-8, and tumor necrosis factor-α. We conclude that the anticancer activity of the newly synthesized NOC15 is 1.36-fold beneficial than NCTD as an anticancer agent and that NOC15 can increase the percentage of cells in the sub-G1 phase through the stimulation of p38 and ERK1/2 of the MAPK signaling pathway and the inhibition of calcineurin expression and IL-2 production. The NOC15 may have the potential of being developed into an anticancer agent in the future.

Show MeSH
Related in: MedlinePlus