Year: 2018
Type: conference-abstract
Abstract: We have previously demonstrated that monoamine oxidase B (MAOB), highly elevated in glioma, may be used to catalytically convert uncharged methyl-tetrahydropyridine (MP-) groups into the mitochondrial targeted, cationic, methyl-pyridinium (P+-) form. Our first generation mitochondrial ‘smart-bomb’, MP-MUS, used a nitrogen mustard ‘warhead’, and was demonstrated to attach glioma mitochondrial DNA in vitro and in vivo. The development of our lead compound into a clinically used therapeutic was hampered by the reactivity of the nitrogen mustard ‘warhead’ and thus the potential of off-target toxicity. We now report our second generation lead compound, MP-Pt(IV), in which we replaced the reactive nitrogen mustard with an unreactive platinum (IV) group. This new ‘warhead’ was designed to undergo ascorbate-linked reductive activation so as to give rise to cis-platin, DNA-crosslinking chemotherapeutic, that will be able to attack gliomal mitochondrial DNA. MP-Pt(IV) is a very good substrate for MAOB, but not MAOA, and is converted by gliomal MAOB into the cationic, lipophilic mitochondrial targeting P+-Pt(IV). The principle biological reductant capable of converting Pt(IV) into cis-platin is ascorbate. We show that gliomas have high levels of mitochondrial ascorbate, and these elevated levels of ascorbate reflect the elevation of glucose/dehydroxyascorbate transporters, GLUT1, GLUT 3, and GLUT4. Here we show that MP-Pt(IV) is highly effective chemotherapeutic, in in vitro as well as in vivo mouse intracranial mouse models of glioblastoma. In vitro studies show that we can potentiate the toxicity of MP-Pt(IV) by increasing mitochondrial ascorbate levels, by incubating cells with dehydroxyascorbate. In an in vivo model, we see that MP-Pt(IV) potentiates the classical chemotherapeutic agent temozolomide and also temozolomide based chemoradiation. Of note is the ability of MP-Pt(IV), like MP-MUS, to cause an elevation in mitochondrial, MAOB levels in treated cells. Treatment of glioma with MP-Pt(IV) creates the opposite of drug resistance, with treating cells becoming increasingly sensitive to MP-Pt(IV).
Source: Neuro-Oncology
Authors: Martyn Sharpe, David Baskin, Sudhir Raghavan
Institution: Houston Methodist
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2899613377