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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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Effects of (a) NCTD and (b) NOC15 with/without PMA plus ION on the cell viability of HNL and Jurkat T cells as assessed using the CCK-8 test. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) were added to the culture media and incubated for 24 h. Cell viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 versus NCTD+PMA plus ION (Jurkat T cell). NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner, and the pretreatment with PMA plus ION can increase the cell viability. The IC50 value of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment was estimated to be 15.6 and 1.4 μmol/l, respectively, and the IC50 of NCTD and NOC15 on HNL was estimated to be 1698.0 and 207.9 μmol/l, respectively. CCK-8, cell counting kit-8; HNL, human normal lymphoblast; IC50, half maximal inhibitory concentration; ION, ionomycin; NCTD, norcantharidin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
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Figure 1: Effects of (a) NCTD and (b) NOC15 with/without PMA plus ION on the cell viability of HNL and Jurkat T cells as assessed using the CCK-8 test. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) were added to the culture media and incubated for 24 h. Cell viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 versus NCTD+PMA plus ION (Jurkat T cell). NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner, and the pretreatment with PMA plus ION can increase the cell viability. The IC50 value of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment was estimated to be 15.6 and 1.4 μmol/l, respectively, and the IC50 of NCTD and NOC15 on HNL was estimated to be 1698.0 and 207.9 μmol/l, respectively. CCK-8, cell counting kit-8; HNL, human normal lymphoblast; IC50, half maximal inhibitory concentration; ION, ionomycin; NCTD, norcantharidin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.

Mentions: To determine the effects of NCTD and NOC15 on the cell viability of Jurkat T cells with/without PMA plus ION, the Jurkat T cells were treated with NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0, 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, respectively. The cell viability was assessed using the CCK-8 test. Figure 1 shows that both NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner. Moreover, the pretreatment with PMA plus ION can increase the viability of Jurkat T cells. The IC50 values of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment were estimated to be 15.6 and 1.4 μmol/l, respectively. Thus, the anticancer effect of NOC15 on Jurkat T cells is 11.14-fold (=15.6÷1.4) more potent than NCTD in terms of cell viability.


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)

Effects of (a) NCTD and (b) NOC15 with/without PMA plus ION on the cell viability of HNL and Jurkat T cells as assessed using the CCK-8 test. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) were added to the culture media and incubated for 24 h. Cell viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 versus NCTD+PMA plus ION (Jurkat T cell). NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner, and the pretreatment with PMA plus ION can increase the cell viability. The IC50 value of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment was estimated to be 15.6 and 1.4 μmol/l, respectively, and the IC50 of NCTD and NOC15 on HNL was estimated to be 1698.0 and 207.9 μmol/l, respectively. CCK-8, cell counting kit-8; HNL, human normal lymphoblast; IC50, half maximal inhibitory concentration; ION, ionomycin; NCTD, norcantharidin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Effects of (a) NCTD and (b) NOC15 with/without PMA plus ION on the cell viability of HNL and Jurkat T cells as assessed using the CCK-8 test. The cells were preincubated for 22 h and stimulated with PMA plus ION for 2 h, and then NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) were added to the culture media and incubated for 24 h. Cell viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 versus NCTD+PMA plus ION (Jurkat T cell). NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner, and the pretreatment with PMA plus ION can increase the cell viability. The IC50 value of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment was estimated to be 15.6 and 1.4 μmol/l, respectively, and the IC50 of NCTD and NOC15 on HNL was estimated to be 1698.0 and 207.9 μmol/l, respectively. CCK-8, cell counting kit-8; HNL, human normal lymphoblast; IC50, half maximal inhibitory concentration; ION, ionomycin; NCTD, norcantharidin; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
Mentions: To determine the effects of NCTD and NOC15 on the cell viability of Jurkat T cells with/without PMA plus ION, the Jurkat T cells were treated with NCTD (0, 2, 4, 15, 30, and 60 μmol/l) or NOC15 (0, 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, respectively. The cell viability was assessed using the CCK-8 test. Figure 1 shows that both NCTD and NOC15 significantly inhibited the growth of Jurkat T cells in a dose-dependent manner. Moreover, the pretreatment with PMA plus ION can increase the viability of Jurkat T cells. The IC50 values of NCTD and NOC15 on Jurkat T cells without PMA plus ION pretreatment were estimated to be 15.6 and 1.4 μmol/l, respectively. Thus, the anticancer effect of NOC15 on Jurkat T cells is 11.14-fold (=15.6÷1.4) more potent than NCTD in terms of cell viability.

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