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

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.

ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

“…After an additional incubation for 24 h, ATP assays and western blots were performed. In parallel assays, after 28 h, cell viability assays using trypan blue ( Dettmer et al, 2015 ) and an LDH cytotoxicity assay were performed ( Sharpe et al, 2015 ).…”

Intracranial Glioblastomas: New Hope for an Effective Treatment

“…Preliminary findings with MP-MUS reported by Sharpe et al (2015--in this issue) are highly encouraging. The authors showed that incubating cultures of human glioblastoma cells with MP-MUS significantly decreased the mitochondrial membrane potential, whereas selegiline, a specific inhibitor of MAOB, did not.…”

“…The work by Sharpe et al (2015--in this issue) may provide just such a strategy. The rationale is relatively simple yet elegant.…”

“…P + -MUS, like MPP + , is highly lipophilic and accumulates in the mitochondrial matrix ( Sharpe et al, 2015a ). Loss of chloride ion from P + -MUS results in conversion of the mustard moiety to a highly reactive substituent (either a 3-membered aziridinium or a 5-membered dihydrooxazolium), which has the ability to cause massive oxidative stress and DNA breaks in the targeted mitochondria ( Sharpe et al, 2015--in this issue ).…”

CNS Anticancer Drug Discovery and Development: 2016 conference insights

“…To better understand the value of MAOB, two strategies were proposed: the use of MAOB to: convert prodrugs into conventional agents, like the MGMT inhibitor O 6 -benzylguanine; and into active agents that target mitochondrial DNA (so-called 'mitochondrial smart bombs'). Both strategies were shown to increase survival in mouse intracranial GBM models [26].…”