# Pharmacological Modulation of Autophagy Can Sensitize Acute Lymphoblastic Leukemia Cell Lines to Dexamethasone

## TL;DR

This study shows that adjusting autophagy levels with drugs can make leukemia cells more responsive to dexamethasone treatment.

## Contribution

The study demonstrates that autophagy modulation can sensitize ALL cell lines to dexamethasone, depending on their baseline autophagy levels.

## Key findings

- Tamoxifen-induced autophagy enhanced dexamethasone sensitivity in most ALL cell lines.
- GC-resistant cell lines showed no autophagy changes after DEX treatment, while sensitive ones showed autophagy linked to cell death.
- Autophagy modulation effects varied by cell line, with some showing increased apoptosis and others reduced proliferation.

## Abstract

Dexamethasone (DEX) is a potent synthetic glucocorticoid (GC) widely used in treatment of acute lymphoblastic leukemia (ALL). Autophagy, a cellular recycling process, may play a dual role in GC resistance: in resistant cells, it often acts as a survival mechanism, whereas in sensitive cells, GC can induce autophagy before cell death. The present study examined how pharmacological modulation of autophagy, both its induction and inhibition, affects GC sensitivity in five ALL cell lines. Induction of autophagy with tamoxifen (TAM) was shown to successfully enhance GC sensitivity in most cell lines. These findings suggest that each ALL cell line may have an optimal basal level of autophagy, and that its dysregulation can effectively increase GC sensitivity.

Background: The potent synthetic glucocorticoid (GC), dexamethasone (DEX), is a highly effective component of conventional chemotherapy for acute lymphoblastic leukemia (ALL). However, cases of GC resistance require elucidation of the underlying mechanisms and the development of new strategies to overcome them. GC-induced autophagy can play a dual role in GC resistance: it often acts as a salvage mechanism in resistant cells, while in sensitive cells, it is a mechanism leading to cell death. Methods: In the present study, cell death and autophagy, as well as their dependence on glucocorticoid receptors (GRs), were simultaneously monitored in DEX-treated ALL cell lines, both sensitive and resistant to GCs. Results: In GC-resistant cell lines, no changes in autophagy levels were observed after DEX treatment, whereas in GC-sensitive cell lines, autophagy elevation was associated with cell death. Blockade of GC receptors completely abolished DEX cytotoxicity in CCRF–CEM cells but not in RS4;11 cells, suggesting the participation of distinct, cell line-specific mechanisms. Furthermore, we investigated how pharmacological modulation of autophagy, both induction and inhibition, affects GC sensitivity. Autophagy induction with tamoxifen (TAM) successfully sensitized most cell lines to DEX. In CCRF–CEM cells, the sensitization effect was shown to correlate with increased apoptosis. In other cell lines, no increase in cell death was observed, suggesting decreased cell proliferation. Conclusions: These results suggest that each ALL cell line may have an optimal basal level of autophagy, and targeted dysregulation of this level may be an effective strategy for enhancing GC sensitivity.