Halofantrine Upregulates ATP6V0D2 and Induces Cytotoxic Autophagy in GBM Models

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
• Halofantrine (halo), an antimalarial drug, has emerged as a potential therapeutic agent for GBM.
• Understanding the mechanism of halo's action in GBM is crucial for its clinical application.

Purpose of the Study:

• To investigate the inhibitory effect of halofantrine (halo) on Glioblastoma (GBM) cells.
• To elucidate the underlying molecular mechanism, focusing on the role of ATP6V0D2 and autophagy.
• To evaluate the therapeutic potential of halo against GBM in preclinical models.

Main Methods:

• Analysis of ATP6V0D2 expression in GBM using The Cancer Genome Atlas (TCGA) and patient samples.
• In vitro studies using U251 GBM cells to assess halo's effect on cell viability, ATP6V0D2 expression, and autophagy.
• Quantitative PCR, Western blot, immunofluorescence, and transmission electron microscopy were employed to analyze molecular and cellular changes.
• Construction of stable ATP6V0D2 knockdown and overexpression models in U251 cells.
• In vivo evaluation of halo's anti-tumor efficacy and mechanism in a U251 cell xenograft mouse model.

Main Results:

• ATP6V0D2 expression was found to be low in GBM patients.
• Halofantrine (halo) treatment upregulated ATP6V0D2 expression and induced cytotoxic autophagy (TA) in U251 cells.
• Knockdown of ATP6V0D2 inhibited halo-mediated autophagy and cytotoxicity, while overexpression enhanced these effects.
• Halo demonstrated significant anti-GBM activity in vivo, consistent with in vitro findings.
• ATP6V0D2 was identified as a key tumor suppressor factor in GBM.

Conclusions:

• Halofantrine (halo) exerts anti-GBM effects by upregulating ATP6V0D2 and promoting cytotoxic autophagy.
• ATP6V0D2 plays a critical role in mediating halo's anti-tumor activity in GBM.
• Further research is needed to assess halo's blood-brain barrier permeability and potential cardiac toxicity.