SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma
Jeffrey Wojton1, Walter Hans Meisen1, Naduparambil K Jacob2
1Department of Neurosurgery, The Ohio State University Medical Center, Columbus, OH.
Abstract:
SapC-DOPS is a novel nanotherapeutic that has been shown to target and induce cell death in a variety of cancers, including glioblastoma (GBM). GBM is a primary brain tumor known to frequently demonstrate resistance to apoptosis-inducing therapeutics. Here we explore the mode of action for SapC-DOPS in GBM, a treatment being developed by Bexion Pharmaceuticals for clinical testing in patients. SapC-DOPS treatment was observed to induce lysosomal dysfunction of GBM cells characterized by decreased glycosylation of LAMP1 and altered proteolytic processing of cathepsin D independent of apoptosis and autophagic cell death. We observed that SapC-DOPS induced lysosomal membrane permeability (LMP) as shown by LysoTracker Red and Acridine Orange staining along with an increase of sphingosine, a known inducer of LMP. Additionally, SapC-DOPS displayed strong synergistic interactions with the apoptosis-inducing agent TMZ. Collectively our data suggest that SapC-DOPS induces lysosomal cell death in GBM cells, providing a new approach for treating tumors resistant to traditional apoptosis-inducing agents.
Insights
SapC-DOPS nanotherapy induces cancer cell death by disrupting lysosomes, not apoptosis. This novel approach shows promise for treating glioblastoma (GBM) resistant to conventional therapies and synergizes with other treatments.
Area of Science:
- Oncology
- Nanomedicine
- Cell Biology
Background:
- Glioblastoma (GBM) frequently exhibits resistance to apoptosis-inducing cancer therapies.
- Novel therapeutic strategies are needed to overcome treatment resistance in GBM.
Purpose of the Study:
- To investigate the mechanism of action of SapC-DOPS, a nanotherapeutic, in glioblastoma cells.
- To determine if SapC-DOPS can overcome apoptosis resistance in GBM.
Main Methods:
- SapC-DOPS treatment of GBM cells.
- Analysis of lysosomal function, including LAMP1 glycosylation and cathepsin D processing.
- Assessment of lysosomal membrane permeability (LMP) using LysoTracker Red and Acridine Orange.
- Evaluation of synergistic effects with temozolomide (TMZ).
Main Results:
- SapC-DOPS induced lysosomal dysfunction in GBM cells, independent of apoptosis or autophagy.
- Lysosomal membrane permeability (LMP) was increased, evidenced by specific staining and elevated sphingosine levels.
- SapC-DOPS demonstrated significant synergistic effects when combined with TMZ.
Conclusions:
- SapC-DOPS triggers cancer cell death through lysosomal disruption in GBM.
- This nanotherapeutic offers a potential new strategy for treating apoptosis-resistant glioblastoma.
- SapC-DOPS exhibits synergistic activity with chemotherapy agents like TMZ.
