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Dual targeting of the mitochondrial Lon peptidase 1 and the chymotrypsin-like proteasome activity as a potential therapeutic strategy in malignant astrocytoma models

  • 0Department of Experimental Pathology & Laboratory Medicine, University of California Irvine, Irvine, CA, USA.
Pharmacological Research +

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March 15, 2025

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March 15, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Malignant astrocytoma treatment is improved by dual inhibition of Mitochondrial Lon Peptidase 1 (LonP1) and Chymotrypsin-like (CT-L) proteasome activity. A novel compound, BT317, shows promise in preclinical models, enhancing temozolomide efficacy.

Area Of Science

  • Oncology
  • Biochemistry
  • Mitochondrial Biology

Background

  • Malignant astrocytomas exhibit hypoxia-driven mitochondrial dysfunction, including altered respiration and increased proteasome activity.
  • Mitochondrial Lon Peptidase 1 (LonP1) overexpression and elevated Chymotrypsin-like (CT-L) proteasome activity are linked to aggressive tumors and poor patient outcomes.
  • Targeting LonP1 or CT-L proteasome activity individually shows preclinical anti-astrocytoma effects.

Purpose Of The Study

  • To investigate the efficacy of dual inhibition of LonP1 and CT-L proteasome activity in malignant astrocytoma.
  • To evaluate a novel small molecule, BT317, as a dual inhibitor of LonP1 and CT-L proteasome activity.
  • To assess the therapeutic potential of BT317, alone and in combination with temozolomide (TMZ), in preclinical models.

Main Methods

  • Utilized established malignant astrocytoma cell lines and patient-derived glioma stem cell-like cultures.
  • Employed gain- and loss-of-function genetic models to elucidate the role of LonP1.
  • Evaluated BT317 in vitro and in an orthotopic xenograft astrocytoma model, assessing synergy with temozolomide.

Main Results

  • Dual inhibition of LonP1 and CT-L proteasome activity induced reactive oxygen species (ROS) and apoptosis in astrocytoma cells.
  • BT317 effectively inhibited both LonP1 and CT-L proteasome activity, demonstrating drug sensitivity driven by LonP1.
  • BT317 showed synergistic activity with temozolomide in vitro and therapeutic efficacy in vivo, crossing the blood-brain barrier.

Conclusions

  • Dual inhibition of LonP1 and CT-L proteasome activity represents a promising therapeutic strategy for malignant astrocytoma.
  • BT317, a novel dual inhibitor, exhibits significant anti-tumor activity and enhances standard chemotherapy efficacy.
  • This preclinical study supports further clinical investigation of BT317 for malignant astrocytoma treatment.

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