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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 MAPK inhibitors on cell viability in NOC15-treated Jurkat T cells. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were incubated with NOC15 (IC50) or without NOC15 at the presence or absence of SB203580 (p38 inhibitor), PD98059 (ERK1/2 inhibitor), and SP600125 (JNK1/2 inhibitor) for 24 h, the cells were collected and the viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 was considered significantly different from PMA plus ION control. #P<0.05 versus PMA plus ION+NOC15 (IC50). The p38 and ERK1/2 inhibitor, but not the JNK1/2 inhibitor, can increase the cell viability of NOC15-treated cells. CCK-8, cell counting kit-8; IC50, half maximal inhibitory concentration; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
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Figure 4: Effects of MAPK inhibitors on cell viability in NOC15-treated Jurkat T cells. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were incubated with NOC15 (IC50) or without NOC15 at the presence or absence of SB203580 (p38 inhibitor), PD98059 (ERK1/2 inhibitor), and SP600125 (JNK1/2 inhibitor) for 24 h, the cells were collected and the viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 was considered significantly different from PMA plus ION control. #P<0.05 versus PMA plus ION+NOC15 (IC50). The p38 and ERK1/2 inhibitor, but not the JNK1/2 inhibitor, can increase the cell viability of NOC15-treated cells. CCK-8, cell counting kit-8; IC50, half maximal inhibitory concentration; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.

Mentions: Figure 1 indicates that NOC15 effectively decreased the cell viability in Jurkat T cells. The expressions of p-p38 and p-ERK1/2 were significantly increased by NOC15 treatment (Fig. 3). Figure 4 further shows that the reduction in cell viability because of NOC15 could be inhibited by p38 inhibitor (SB203580) and ERK1/2 inhibitor (PD98059), but not by JNK1/2 inhibitor (SP600125).


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 MAPK inhibitors on cell viability in NOC15-treated Jurkat T cells. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were incubated with NOC15 (IC50) or without NOC15 at the presence or absence of SB203580 (p38 inhibitor), PD98059 (ERK1/2 inhibitor), and SP600125 (JNK1/2 inhibitor) for 24 h, the cells were collected and the viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 was considered significantly different from PMA plus ION control. #P<0.05 versus PMA plus ION+NOC15 (IC50). The p38 and ERK1/2 inhibitor, but not the JNK1/2 inhibitor, can increase the cell viability of NOC15-treated cells. CCK-8, cell counting kit-8; IC50, half maximal inhibitory concentration; ION, ionomycin; MAPK, mitogen-activated protein kinase; 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 4: Effects of MAPK inhibitors on cell viability in NOC15-treated Jurkat T cells. The cells were preincubated for 22 h and then stimulated with PMA plus ION for 2 h. After the cells were incubated with NOC15 (IC50) or without NOC15 at the presence or absence of SB203580 (p38 inhibitor), PD98059 (ERK1/2 inhibitor), and SP600125 (JNK1/2 inhibitor) for 24 h, the cells were collected and the viability was calculated using the CCK-8 test. The results are expressed as means±SD for six independent experiments. *P<0.05 was considered significantly different from PMA plus ION control. #P<0.05 versus PMA plus ION+NOC15 (IC50). The p38 and ERK1/2 inhibitor, but not the JNK1/2 inhibitor, can increase the cell viability of NOC15-treated cells. CCK-8, cell counting kit-8; IC50, half maximal inhibitory concentration; ION, ionomycin; MAPK, mitogen-activated protein kinase; NOC15, N-farnesyloxy-norcantharimide; PMA, phorbol 12-myristate 13-acetate.
Mentions: Figure 1 indicates that NOC15 effectively decreased the cell viability in Jurkat T cells. The expressions of p-p38 and p-ERK1/2 were significantly increased by NOC15 treatment (Fig. 3). Figure 4 further shows that the reduction in cell viability because of NOC15 could be inhibited by p38 inhibitor (SB203580) and ERK1/2 inhibitor (PD98059), but not by JNK1/2 inhibitor (SP600125).

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