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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

MP-MUS induces ROS and causes LDHA and mitochondrial upregulation.(A) Increase in oxidative stress; representative images of glioma labeled for hydrazine reactive aldehydes/ketones (I), ddTUNEL (II), peroxides (III) hydroxyl radical (IV) all labeled green, with MAOB labeled red. The final panel shows the levels of LDHA (V). The arrows point to cells with massive oxidative stress.(B) MP-MUS increases levels of oxidative stress, DNA breaks, mitochondrial enzymes, and LDHA.(C) 3′OH DNA lesions caused by MP-MUS are colocalized with mitochondrial MAOB, and are exclusively cytosolic and non-nuclear.
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f0020: MP-MUS induces ROS and causes LDHA and mitochondrial upregulation.(A) Increase in oxidative stress; representative images of glioma labeled for hydrazine reactive aldehydes/ketones (I), ddTUNEL (II), peroxides (III) hydroxyl radical (IV) all labeled green, with MAOB labeled red. The final panel shows the levels of LDHA (V). The arrows point to cells with massive oxidative stress.(B) MP-MUS increases levels of oxidative stress, DNA breaks, mitochondrial enzymes, and LDHA.(C) 3′OH DNA lesions caused by MP-MUS are colocalized with mitochondrial MAOB, and are exclusively cytosolic and non-nuclear.

Mentions: In addition to damaging glioblastoma mtDNA, MP-MUS increased the levels of mitochondrial ROS (Fig. 4). In addition, exposure of cells to 90 μM MP-MUS increased mitochondrial MitoTracker™ labeling and lactate dehydrogenase A (LDHA) levels. The levels of mitochondrial proteins cytochrome c (columns I–II) and MAOB (columns III–IV) (Fig. 4A, labeled in red) increased by 70% and 130% (plotted in Fig. 4B). The increased mitochondrial levels were accompanied by a 4.8-fold increase in LDHA levels (column V, red). These changes in protein levels were consistent with the increased mitochondrial respiratory chain activity and increased LDH activity, per cell, following exposure to MP-MUS (Fig. 3).


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)

MP-MUS induces ROS and causes LDHA and mitochondrial upregulation.(A) Increase in oxidative stress; representative images of glioma labeled for hydrazine reactive aldehydes/ketones (I), ddTUNEL (II), peroxides (III) hydroxyl radical (IV) all labeled green, with MAOB labeled red. The final panel shows the levels of LDHA (V). The arrows point to cells with massive oxidative stress.(B) MP-MUS increases levels of oxidative stress, DNA breaks, mitochondrial enzymes, and LDHA.(C) 3′OH DNA lesions caused by MP-MUS are colocalized with mitochondrial MAOB, and are exclusively cytosolic and non-nuclear.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0020: MP-MUS induces ROS and causes LDHA and mitochondrial upregulation.(A) Increase in oxidative stress; representative images of glioma labeled for hydrazine reactive aldehydes/ketones (I), ddTUNEL (II), peroxides (III) hydroxyl radical (IV) all labeled green, with MAOB labeled red. The final panel shows the levels of LDHA (V). The arrows point to cells with massive oxidative stress.(B) MP-MUS increases levels of oxidative stress, DNA breaks, mitochondrial enzymes, and LDHA.(C) 3′OH DNA lesions caused by MP-MUS are colocalized with mitochondrial MAOB, and are exclusively cytosolic and non-nuclear.
Mentions: In addition to damaging glioblastoma mtDNA, MP-MUS increased the levels of mitochondrial ROS (Fig. 4). In addition, exposure of cells to 90 μM MP-MUS increased mitochondrial MitoTracker™ labeling and lactate dehydrogenase A (LDHA) levels. The levels of mitochondrial proteins cytochrome c (columns I–II) and MAOB (columns III–IV) (Fig. 4A, labeled in red) increased by 70% and 130% (plotted in Fig. 4B). The increased mitochondrial levels were accompanied by a 4.8-fold increase in LDHA levels (column V, red). These changes in protein levels were consistent with the increased mitochondrial respiratory chain activity and increased LDH activity, per cell, following exposure to MP-MUS (Fig. 3).

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