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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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Expression of MAPKs and p-MAPKs in NOC15-treated Jurkat T cells. (a) Western blot. (b) Relative expression. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were treated by NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, the cells were collected, lysed, and the proteins were extracted for western blot analysis. The β-actin was used as the internal control. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. The expressions of p-p38 and p-ERK1/2 were significantly increased in a dose-dependent manner. ERK1/2, phospho-extracellular signal-regulated protein kinase 1/2; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
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Figure 3: Expression of MAPKs and p-MAPKs in NOC15-treated Jurkat T cells. (a) Western blot. (b) Relative expression. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were treated by NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, the cells were collected, lysed, and the proteins were extracted for western blot analysis. The β-actin was used as the internal control. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. The expressions of p-p38 and p-ERK1/2 were significantly increased in a dose-dependent manner. ERK1/2, phospho-extracellular signal-regulated protein kinase 1/2; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.

Mentions: Western blot was used to detect the expression of MAPKs and p-MAPKs in Jurkat T cells. As shown in Fig. 3a, the expressions of p-p38 and p-ERK1/2 were markedly increased in a dose-dependent manner by treatment with 0.5–4 μmol/l NOC15. Figure 3b shows that the expressions of p38, ERK1/2, and JNK1/2 were not significantly changed by NOC15 treatment, and that the expressions of p-p38 and p-ERK1/2 were significantly increased comparing with the untreated control. However, the p-JNK1/2 expression was not altered by NOC15 treatment (Fig. 3b).


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)

Expression of MAPKs and p-MAPKs in NOC15-treated Jurkat T cells. (a) Western blot. (b) Relative expression. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were treated by NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, the cells were collected, lysed, and the proteins were extracted for western blot analysis. The β-actin was used as the internal control. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. The expressions of p-p38 and p-ERK1/2 were significantly increased in a dose-dependent manner. ERK1/2, phospho-extracellular signal-regulated protein kinase 1/2; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
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Related In: Results  -  Collection

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

Figure 3: Expression of MAPKs and p-MAPKs in NOC15-treated Jurkat T cells. (a) Western blot. (b) Relative expression. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were treated by NOC15 (0. 0.25, 0.5, 1, 2, and 4 μmol/l) for 24 h, the cells were collected, lysed, and the proteins were extracted for western blot analysis. The β-actin was used as the internal control. The results are expressed as means±SD for three independent experiments. *P<0.05 versus untreated control. The expressions of p-p38 and p-ERK1/2 were significantly increased in a dose-dependent manner. ERK1/2, phospho-extracellular signal-regulated protein kinase 1/2; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
Mentions: Western blot was used to detect the expression of MAPKs and p-MAPKs in Jurkat T cells. As shown in Fig. 3a, the expressions of p-p38 and p-ERK1/2 were markedly increased in a dose-dependent manner by treatment with 0.5–4 μmol/l NOC15. Figure 3b shows that the expressions of p38, ERK1/2, and JNK1/2 were not significantly changed by NOC15 treatment, and that the expressions of p-p38 and p-ERK1/2 were significantly increased comparing with the untreated control. However, the p-JNK1/2 expression was not altered by NOC15 treatment (Fig. 3b).

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