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Updated: Apr 30, 2026
Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis
Published on: November 14, 2025
Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death
A Kondratskyi1, M Yassine1, C Slomianny1
1Inserm U-1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve d'Ascq, France.
Abstract:
The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy.
Insights
ML-9, an Akt kinase inhibitor, uniquely targets autophagy by stimulating formation and inhibiting degradation. This dual action induces prostate cancer cell death and enhances chemotherapy efficacy, offering a novel cancer therapy approach.
Area of Science:
- Oncology
- Cell Biology
- Molecular Pharmacology
Background:
- Autophagy inhibition enhances cancer therapy efficacy with Akt kinase inhibitors.
- ML-9 is a known inhibitor of Akt kinase, myosin light-chain kinase (MLCK), and stromal interaction molecule 1 (STIM1).
Purpose of the Study:
- To investigate the complex role of ML-9 in autophagy.
- To evaluate ML-9 as a potential monotherapy and adjuvant in cancer treatment.
Main Methods:
- Investigated ML-9's effect on autophagy by assessing autophagosome formation and degradation.
- Utilized prostate cancer cell lines for monotherapy and combination studies with docetaxel.
Main Results:
- ML-9 stimulates autophagosome formation via Akt/mammalian target of rapamycin (mTOR) pathway downregulation.
- ML-9 inhibits autophagosome degradation by increasing lysosomal pH, acting as a lysosomotropic agent.
- ML-9 monotherapy induced prostate cancer cell death with autophagic vacuole accumulation.
- ML-9 enhanced docetaxel's anticancer activity, suggesting adjuvant potential.
Conclusions:
- ML-9 exhibits a dual role in autophagy, stimulating formation and inhibiting degradation.
- ML-9 is a promising agent for cancer therapy, targeting both the Akt pathway and autophagy.
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