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Micheliolide derivative DMAMCL inhibits glioma cell growth in vitro and in vivo.

An Y, Guo W, Li L, Xu C, Yang D, Wang S, Lu Y, Zhang Q, Zhai J, Fan H, Qiu C, Qi J, Chen Y, Yuan S - PLoS ONE (2015)

Bottom Line: DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner.Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma.Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity.

View Article: PubMed Central - PubMed

Affiliation: Clinical Laboratory Center, Chinese PLA Air Force General Hospital, Haidian, Beijing 100142, PR China.

ABSTRACT

Background: There is no highly effective chemotherapy for malignant gliomas to date. We found that dimethylaminomicheliolide (DMAMCL), a selective inhibitor of acute myeloid leukemia (AML) stem/progenitor cells, inhibited the growth of glioma cells.

Methods: The distribution of DMAMCL in brain was analyzed by an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) system. The anti-tumor evaluations of DMAMCL in vitro were performed by MTT, FACS and RT-PCR. In vivo, the mixture of C6 cells and matrigel was injected into caudatum, and the anti-tumor activity of DMAMCL was evaluated by tumor growth and rat survival. The toxicity of DMAMCL was evaluated by body weight, daily food intake, hematological or serum biochemical analyses, and histological appearance of tissues.

Results: The IC50 values of DMAMCL against the C6 and U-87MG cell lines in vitro were 27.18 ± 1.89 μM and 20.58 ± 1.61 μM, respectively. DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner. In a C6 rat tumor model, daily administration of DMAMCL for 21 days reduced the burden of C6 tumors by 60% to 88% compared to controls, and more than doubled the mean lifespan of tumor-bearing rats. Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma. Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity.

Conclusions: These results suggest that DMAMCL is highly promising for the treatment of glioma.

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Related in: MedlinePlus

Biodistribution of DMAMCL administered orally.DMAMCL concentrations over time in rats after a single oral dose (100 mg/kg) (n = 6) in plasma, brain, spleen, lung, kidney, heart and liver were detected by UPLC-MS/MS. Statistical significance between plasma and brain is indicated by asterisks (*p < 0.01 compared to vehicle; **p < 0.01 compared to vehicle).
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pone.0116202.g002: Biodistribution of DMAMCL administered orally.DMAMCL concentrations over time in rats after a single oral dose (100 mg/kg) (n = 6) in plasma, brain, spleen, lung, kidney, heart and liver were detected by UPLC-MS/MS. Statistical significance between plasma and brain is indicated by asterisks (*p < 0.01 compared to vehicle; **p < 0.01 compared to vehicle).

Mentions: To measure the biodistribution of DMAMCL in rats, a single oral dose of an aqueous DMAMCL solution (100 mg/kg) was given, and the concentration of DMAMCL was determined in the plasma, liver, lung, kidney, and brain at different times (Fig. 2). The equations of calibration curve of DMAMCL were y = 0.012 x+0.0065 (n = 5) with r2 = 0.9972 (a correlation coefficients) in plasma, y = 0.0024 x+0.0172 (n = 5) with r2 = 0.9977 in brain, y = 0.00168 x + 0.0174 (n = 5) with r2 = 0.9968 in liver, y = 0.0058 x+0.158 (n = 5) with r2 = 0.9945 in kidney, y = 0.00646 x+0.028 (n = 5) with r2 = 0.9965 in spleen, y = 0.0034 x+0.0276 (n = 5) with r2 = 0.9982 in lung, and y = 0.00343 x+0.0341 (n = 5) with r2 = 0.9955 in heart, respectively. The recoveries in all tissues were ranged from 89.35% to 115.1%. The RSD of inter-day and intra-day was less than 10%. The results of biodistribution are shown in Fig. 2. The data revealed that DMAMCL accumulated and was dramatically higher in almost all tissues than in plasma. Importantly, in rat brain, DMAMCL was detectable and quickly reached a peak concentration of 18970 ± 9603 ng/ml at 0.5 hours after administration. More significantly, DMAMCL could still remain a higher concentration of 4913 ± 869 ng/ml for a longer period of time (3 hours) than in plasma (2566 ± 968 ng/ml). On the other hand, the fraction of C brain / C plasma, an important index to evaluate drugs entering brain, represents the concentration ratio in brain and plasma[22, 23], can be used to evaluate the BBB penetration of drugs. Briefly, the larger the fraction is, the higher the concentration of DMAMCL accumulated in brain. The ratios of C brain / C plasma >1 represent a high ratio and indicate that a compound has a high BBB crossing. Therefore, we calculated the C brain / C plasma of DMAMCL. As shown in table 1, the relatively high ratios of C brain / C plasma revealed that DMAMCL could easily cross BBB and accumulate in the brain.


Micheliolide derivative DMAMCL inhibits glioma cell growth in vitro and in vivo.

An Y, Guo W, Li L, Xu C, Yang D, Wang S, Lu Y, Zhang Q, Zhai J, Fan H, Qiu C, Qi J, Chen Y, Yuan S - PLoS ONE (2015)

Biodistribution of DMAMCL administered orally.DMAMCL concentrations over time in rats after a single oral dose (100 mg/kg) (n = 6) in plasma, brain, spleen, lung, kidney, heart and liver were detected by UPLC-MS/MS. Statistical significance between plasma and brain is indicated by asterisks (*p < 0.01 compared to vehicle; **p < 0.01 compared to vehicle).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4320118&req=5

pone.0116202.g002: Biodistribution of DMAMCL administered orally.DMAMCL concentrations over time in rats after a single oral dose (100 mg/kg) (n = 6) in plasma, brain, spleen, lung, kidney, heart and liver were detected by UPLC-MS/MS. Statistical significance between plasma and brain is indicated by asterisks (*p < 0.01 compared to vehicle; **p < 0.01 compared to vehicle).
Mentions: To measure the biodistribution of DMAMCL in rats, a single oral dose of an aqueous DMAMCL solution (100 mg/kg) was given, and the concentration of DMAMCL was determined in the plasma, liver, lung, kidney, and brain at different times (Fig. 2). The equations of calibration curve of DMAMCL were y = 0.012 x+0.0065 (n = 5) with r2 = 0.9972 (a correlation coefficients) in plasma, y = 0.0024 x+0.0172 (n = 5) with r2 = 0.9977 in brain, y = 0.00168 x + 0.0174 (n = 5) with r2 = 0.9968 in liver, y = 0.0058 x+0.158 (n = 5) with r2 = 0.9945 in kidney, y = 0.00646 x+0.028 (n = 5) with r2 = 0.9965 in spleen, y = 0.0034 x+0.0276 (n = 5) with r2 = 0.9982 in lung, and y = 0.00343 x+0.0341 (n = 5) with r2 = 0.9955 in heart, respectively. The recoveries in all tissues were ranged from 89.35% to 115.1%. The RSD of inter-day and intra-day was less than 10%. The results of biodistribution are shown in Fig. 2. The data revealed that DMAMCL accumulated and was dramatically higher in almost all tissues than in plasma. Importantly, in rat brain, DMAMCL was detectable and quickly reached a peak concentration of 18970 ± 9603 ng/ml at 0.5 hours after administration. More significantly, DMAMCL could still remain a higher concentration of 4913 ± 869 ng/ml for a longer period of time (3 hours) than in plasma (2566 ± 968 ng/ml). On the other hand, the fraction of C brain / C plasma, an important index to evaluate drugs entering brain, represents the concentration ratio in brain and plasma[22, 23], can be used to evaluate the BBB penetration of drugs. Briefly, the larger the fraction is, the higher the concentration of DMAMCL accumulated in brain. The ratios of C brain / C plasma >1 represent a high ratio and indicate that a compound has a high BBB crossing. Therefore, we calculated the C brain / C plasma of DMAMCL. As shown in table 1, the relatively high ratios of C brain / C plasma revealed that DMAMCL could easily cross BBB and accumulate in the brain.

Bottom Line: DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner.Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma.Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity.

View Article: PubMed Central - PubMed

Affiliation: Clinical Laboratory Center, Chinese PLA Air Force General Hospital, Haidian, Beijing 100142, PR China.

ABSTRACT

Background: There is no highly effective chemotherapy for malignant gliomas to date. We found that dimethylaminomicheliolide (DMAMCL), a selective inhibitor of acute myeloid leukemia (AML) stem/progenitor cells, inhibited the growth of glioma cells.

Methods: The distribution of DMAMCL in brain was analyzed by an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) system. The anti-tumor evaluations of DMAMCL in vitro were performed by MTT, FACS and RT-PCR. In vivo, the mixture of C6 cells and matrigel was injected into caudatum, and the anti-tumor activity of DMAMCL was evaluated by tumor growth and rat survival. The toxicity of DMAMCL was evaluated by body weight, daily food intake, hematological or serum biochemical analyses, and histological appearance of tissues.

Results: The IC50 values of DMAMCL against the C6 and U-87MG cell lines in vitro were 27.18 ± 1.89 μM and 20.58 ± 1.61 μM, respectively. DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner. In a C6 rat tumor model, daily administration of DMAMCL for 21 days reduced the burden of C6 tumors by 60% to 88% compared to controls, and more than doubled the mean lifespan of tumor-bearing rats. Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma. Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity.

Conclusions: These results suggest that DMAMCL is highly promising for the treatment of glioma.

Show MeSH
Related in: MedlinePlus