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Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS - EBioMedicine (2015)

Bottom Line: Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone.MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB.We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.

ABSTRACT
The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

No MeSH data available.


Related in: MedlinePlus

LD50 of MP-MUS in primary human glioma.(A) Changes in live cell numbers and %dead cells following 24 hour incubation with increasing concentrations of MP-MUS indicate an LD50 of ≈ 80 μM MP-MUS. Mean ± SEM, n = 4 individual wells.(B) LDH and XTT formazan assays performed on other half of the 96-well plate appear to demonstrate an increase in levels of both XTT reduction and LDH, per living cell. Mean ± SEM, n = 8 individual wells.
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f0015: LD50 of MP-MUS in primary human glioma.(A) Changes in live cell numbers and %dead cells following 24 hour incubation with increasing concentrations of MP-MUS indicate an LD50 of ≈ 80 μM MP-MUS. Mean ± SEM, n = 4 individual wells.(B) LDH and XTT formazan assays performed on other half of the 96-well plate appear to demonstrate an increase in levels of both XTT reduction and LDH, per living cell. Mean ± SEM, n = 8 individual wells.

Mentions: We examined the concentration range at which MP-MUS affected the viability of glioma cells. Cells were cultured in a 96-well plate for 24 h. Viability was assessed by counting cells using fluorescence microscopy, measuring the levels of mitochondrial complexes I and III using the XTT assay, and measuring the levels of detergent-permeabilized lactate dehydrogenase. Hoechst staining showed that the LD50 of MP-MUS was 77 μM after 24 h in primary human glioma cultures (Fig. 3A), whereas the LD50 was 50 μM at 48 h (data not shown).


Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

Sharpe MA, Livingston AD, Gist TL, Ghosh P, Han J, Baskin DS - EBioMedicine (2015)

LD50 of MP-MUS in primary human glioma.(A) Changes in live cell numbers and %dead cells following 24 hour incubation with increasing concentrations of MP-MUS indicate an LD50 of ≈ 80 μM MP-MUS. Mean ± SEM, n = 4 individual wells.(B) LDH and XTT formazan assays performed on other half of the 96-well plate appear to demonstrate an increase in levels of both XTT reduction and LDH, per living cell. Mean ± SEM, n = 8 individual wells.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588367&req=5

f0015: LD50 of MP-MUS in primary human glioma.(A) Changes in live cell numbers and %dead cells following 24 hour incubation with increasing concentrations of MP-MUS indicate an LD50 of ≈ 80 μM MP-MUS. Mean ± SEM, n = 4 individual wells.(B) LDH and XTT formazan assays performed on other half of the 96-well plate appear to demonstrate an increase in levels of both XTT reduction and LDH, per living cell. Mean ± SEM, n = 8 individual wells.
Mentions: We examined the concentration range at which MP-MUS affected the viability of glioma cells. Cells were cultured in a 96-well plate for 24 h. Viability was assessed by counting cells using fluorescence microscopy, measuring the levels of mitochondrial complexes I and III using the XTT assay, and measuring the levels of detergent-permeabilized lactate dehydrogenase. Hoechst staining showed that the LD50 of MP-MUS was 77 μM after 24 h in primary human glioma cultures (Fig. 3A), whereas the LD50 was 50 μM at 48 h (data not shown).

Bottom Line: Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone.MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB.We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Kenneth R. Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, 6565 Fannin, Suite 944, Houston, TX 77030, United States.

ABSTRACT
The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

No MeSH data available.


Related in: MedlinePlus