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Updated: Jun 22, 2025
Establishment of an Extracellular Acidic pH Culture System
Published on: November 19, 2017
Ophiobolin A derivatives with enhanced activities under tumor-relevant acidic conditions
Vladimir A Maslivetc1, Md Nabiul Hasan2, Angela Boari3
1Department of Chemistry and Biochemistry, Texas State University, 601 University Dr., San Marcos, TX 78666, USA.
Abstract:
Glioblastoma (GBM) is the most common form of malignant primary brain tumor and is one of the most lethal cancers. The difficulty in treating GBM stems from its highly developed mechanisms of drug resistance. Our research team has recently identified the fungal secondary metabolite ophiobolin A (OpA) as an agent with significant activity against drug-resistant GBM cells. However, the OpA's mode of action is likely based on covalent modification of its intracellular target(s) and thus possible off-target reactivity needs to be addressed. This work involves the investigation of an acid-sensitive OpA analogue approach that exploits the elevated acidity of the GBM microenvironment to enhance the selectivity for tumor targeting. This project identified analogues that showed selectivity at killing GBM cells grown in cultures at reduced pH compared to those maintained under normal neutral conditions. These studies are expected to facilitate the development of OpA as an anti-GBM agent by investigating its potential use in an acid-sensitive analogue form with enhanced selectivity for tumor targeting.
Insights
Researchers explored ophiobolin A analogues to target drug-resistant glioblastoma (GBM). Acid-sensitive analogues showed selective killing of GBM cells in acidic environments, offering a promising strategy for enhanced tumor targeting.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Glioblastoma (GBM) is a lethal primary brain tumor with significant drug resistance.
- Current treatments are limited by GBM's resistance mechanisms.
- Ophiobolin A (OpA), a fungal metabolite, shows activity against drug-resistant GBM cells.
Purpose of the Study:
- To investigate acid-sensitive ophiobolin A (OpA) analogues for targeted glioblastoma (GBM) therapy.
- To exploit the acidic GBM microenvironment for enhanced drug selectivity.
- To address potential off-target reactivity of OpA.
Main Methods:
- Synthesis and evaluation of acid-sensitive OpA analogues.
- Assessment of GBM cell viability in cultures at varying pH levels.
- Comparative analysis of analogue activity in acidic versus neutral conditions.
Main Results:
- Identified OpA analogues demonstrating selective cytotoxicity against GBM cells.
- Observed enhanced killing of GBM cells in acidic culture conditions compared to neutral conditions.
- Demonstrated pH-dependent selectivity of the developed analogues.
Conclusions:
- Acid-sensitive OpA analogues offer a strategy for selective GBM targeting.
- Exploiting the acidic tumor microenvironment can improve therapeutic efficacy.
- Further development of these analogues holds potential for novel anti-GBM therapies.
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