N-Farnesyloxy-norcantharimide and N-farnesyl-norcantharimide inhibit the progression of leukemia and increase survival days in a syngeneic mouse leukemia model

Chang, Ming-Hong; Tsai, En-Tung; Wu, Jin‐Yi; Liao, Hui-Fen; Chen, Yu-Jen; Kuo, Cheng‐Deng

doi:10.1097/cad.0000000000000210

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Tail vein injection was performed with 1 × 10 6 cells/mouse. Through the detection of the number of white blood cells (WBC) in peripheral blood (PB) as well as the leukemia cell infiltration, whether mouse models of leukemia were successfully established was detected (Chang et al, , Trifirò et al, ). The mice models were randomly assigned into the model group, negative control (NC) group, HOTAIR mimics group (transfected with HOTAIR mimics, a nucleic acid sequence enhancing the expression of HOTAIR; Ji, Wuerkenbieke, He, & Ding, ), small interfering RNA (siRNA) HOTAIR group (transfected with siRNA targeting HOTAIR, a nucleic acid sequence reducing the expression of HOTAIR), xav‐939 (the Wnt/β‐catenin signaling pathway inhibitor) group, and HOTAIR mimics + xav‐939 group, with a normal group (10 mice with tail vein injection of 0.1 ml normal saline) acting as the control.…”

Section: Methodsmentioning

confidence: 99%

Long‐noncoding RNA HOTAIR inhibits immunologic rejection of mouse leukemia cells through activating the Wnt/β‐catenin signaling pathway in a mouse model of leukemia

Ding

Dong

2019

Journal Cellular Physiology

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Long‐noncoding RNAs (lncRNAs) is involved in the development of diverse diseases, including leukemia, while the role lncRNA HOX transcript antisense RNA (HOTAIR) played in leukemia remains unclear and in need of further investigation. Therefore, this study was conducted to explore the effects of lncRNA HOTAIR on the immunologic rejection of leukemia cells through the Wnt/β‐catenin in mice. Mice were administrated with HOTAIR mimics as well as small interfering RNA HOTAIR to explore the regulatory role of HOTAIR. The numbers of white blood cell (WBC) and platelet (PLT) and the content of hemoglobin in peripheral blood (PB) were determined. The cytokine level in PB was measured. T‐lymphocyte proliferation activity, Ig production by B cells, natural killer (NK) cell activity, and the proportion of cluster of differentiation 4 (CD4)/CD8 T cell subsets were detected. Expression of HOTAIR, β‐catenin, cyclinD1, GSK‐3β, and c‐Myc in bone marrow was determined. It was revealed that the WBC number increased, while the PLT number along with the hemoglobin content in PB decreased with the upregulated HOTAIR. Additionally, elevated HOTAIR led to decreased levels of transforming growth factor‐β, interferon‐γ, interleukin‐10, and tumor necrosis factor‐α in PB, proliferation activity in T‐lymphocyte, and inhibited Ig production, NK cell activity, and the ratio of CD4/CD8 T cell subsets in B‐lymphocyte. Furthermore, Wnt/β‐catenin was activated by overexpressing HOTAIR. Enhanced survival and proliferation were shown with increased expression of cyclinD1, GSK‐3β, and c‐Myc in the bone marrow of mice induced by overexpressing HOTAIR. These results indicate that restored HOTAIR reduces the immunologic rejection of leukemia cells in mice by activating Wnt/β‐catenin pathway.

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Section: Methodsmentioning

confidence: 99%

Long‐noncoding RNA HOTAIR inhibits immunologic rejection of mouse leukemia cells through activating the Wnt/β‐catenin signaling pathway in a mouse model of leukemia

Ding

Dong

2019

Journal Cellular Physiology

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“…NOC15 was obtained as a colorless liquid; the details of the 1 H and 13 C NMR spectra have been described in a previous report. The molecular weight for C 23 H 33 NO 4 calculated using LC-MS (ESI + , m/z ) is 387.24, found for 410.21 [M+Na] + 26 , 27 .…”

Section: Methodsmentioning

confidence: 99%

“…N -Farnesyloxy-norcantharimide (NOC15, C 23 H 33 NO 4 ), which is a newly synthesized NCTD derivative with the N -farnesyloxy group, has high anticancer activity toward hepatocellular carcinoma, bladder carcinoma, colorectal adenocarcinoma, and acute promyelocytic leukemia 26 . NOC15 also has anticancer efficacy in a syngeneic mouse leukemia model by increasing the survival of mice and decreasing the tumor weight 27 . However, the anticancer mechanism of NOC15 is not clear.…”

Section: Introductionmentioning

confidence: 99%

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

Chang

Wu²,

Liao

et al. 2015

Anti-Cancer Drugs

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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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“…[ 17 ] Both NOC15 and NC15 have higher anticancer activities against hepatocellular carcinoma, bladder carcinoma, colorectal adenocarcinoma, and acute promyelocytic leukemia than NCTD, [ 17 ] and can increase the survival days of mice, decrease the tumor weight, and retard the decrease in the weight of the spleen in a syngeneic mouse leukemia model. [ 18 ]…”

Section: Introductionmentioning

confidence: 99%

Comparative assessment of therapeutic safety of norcantharidin, N-farnesyloxy-norcantharimide, and N-farnesyl-norcantharimide against Jurkat T cells relative to human normal lymphoblast

Chang

Wu²,

Liao

et al. 2016

Medicine

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The therapeutic safety of an anticancer drug is one of the most important concerns of the physician treating the cancer patient. Half maximal inhibitory concentration (IC50) and hillslope are usually used to represent the strength and sensitivity of an anticancer drug on cancer cells. The therapeutic safety of the anticancer drug can be assessed by comparing the IC50 and hillslope of anticancer drugs on cancer cells relative to normal cells. Since there are situations where “more anticancer activity” implies “more toxicity,” the safety of an anticancer drug in these situations is hard to evaluate by using IC50 and hillslope alone. In a previous study, the “net effect” index was devised to represent the net therapeutic effects of one anticancer drug relative to the other. However, the therapeutic safety of one specific anticancer drug alone was not defined in the “net effect” index. This study introduced the “safety index (SI)” to quantify the degree of safety of an anticancer drug by using 4-parameter logistic model on cancer cells relative to normal cells. The therapeutic safety of norcantharidin (NCTD), N-farnesyloxy-norcantharimide (NOC15), and N-farnesyl-norcantharimide (NC15) in the treatment of Jurkat T cells relative to human normal lymphoblast was compared using the newly defined SI. We found that the SI of NOC15 and NC15 was significantly higher than that of NCTD, suggesting that both NOC15 and NC15 can damage more cancer cells and less normal cells than NCTD. We conclude that both NOC15 and NC15 are safer anticancer drugs than NCTD in the treatment of Jurkat T cells relative to human normal lymphoblast. The SI can be further applied to the screening, developments, and applications of anticancer drugs in the future.

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N-Farnesyloxy-norcantharimide and N-farnesyl-norcantharimide inhibit the progression of leukemia and increase survival days in a syngeneic mouse leukemia model

Cited by 6 publications

References 23 publications

Long‐noncoding RNA HOTAIR inhibits immunologic rejection of mouse leukemia cells through activating the Wnt/β‐catenin signaling pathway in a mouse model of leukemia

Long‐noncoding RNA HOTAIR inhibits immunologic rejection of mouse leukemia cells through activating the Wnt/β‐catenin signaling pathway in a mouse model of leukemia

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

Comparative assessment of therapeutic safety of norcantharidin, N-farnesyloxy-norcantharimide, and N-farnesyl-norcantharimide against Jurkat T cells relative to human normal lymphoblast

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