Autolysosomal activation combined with lysosomal destabilization efficiently targets myeloid leukemia cells for cell death

Frontiers in Oncology, vol. 13, pp. 999738

Abstract

Introduction Current cancer research has led to a renewed interest in exploring lysosomal membrane permeabilization and lysosomal cell death as a targeted therapeutic approach for cancer treatment. Evidence suggests that differences in lysosomal biogenesis between cancer and normal cells might open a therapeutic window. Lysosomal membrane stability may be affected by the so-called ‘busy lysosomal behaviour’ characterized by higher lysosomal abundance and activity and more intensive fusion or interaction with other vacuole compartments. Methods We used a panel of multiple myeloid leukemia (ML) cell lines as well as leukemic patient samples and updated methodology to study auto-lysosomal compartment, lysosomal membrane permeabilization and lysosomal cell death. Results Our analyses demonstrated several-fold higher constitutive autolysosomal activity in ML cells as compared to human CD34+ hematopoietic cells. Importantly, we identified mefloquine as a selective activator of ML cells' lysosomal biogenesis, which induced a sizeable increase in ML lysosomal mass, acidity as well as cathepsin B and L activity. Concomitant mTOR inhibition synergistically increased lysosomal activity and autolysosomal fusion and simultaneously decreased the levels of key lysosomal stabilizing proteins, such as LAMP-1 and 2. Discussion In conclusion, mefloquine treatment combined with mTOR inhibition synergistically induced targeted ML cell death without additional toxicity. Taken together, these data provide a molecular mechanism and thus a rationale for a therapeutic approach for specific targeting of ML lysosomes.

Authors 7

1. Harshit Shah

   Medizinische Hochschule Hannover

   Affiliation as printed

   Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany

2. Metodi V. Stankov

   Medizinische Hochschule Hannover

   Affiliation as printed

   Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany

3. Diana Panayotova‐Dimitrova Aachen Department of Dermatology and Allergology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Dermatology and Allergology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany

4. Amir Yazdi Aachen Department of Dermatology and Allergology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Dermatology and Allergology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH), Aachen, Germany

5. Ramachandramouli Budida

   Medizinische Hochschule Hannover

   Affiliation as printed

   Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany

6. Jan‐Henning Klusmann

   Goethe University Frankfurt

   Affiliation as printed

   Pediatric Hematology and Oncology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt (Main), Germany

7. Georg M. N. Behrens corresponding

   Medizinische Hochschule Hannover

   Affiliation as printed

   Department for Rheumatology and Immunology, Hannover Medical School, Hannover, Germany