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Published on: September 1, 2018
Deciphering molecular mechanisms of arginine deiminase-based therapy - Comparative response analysis in paired human
Claudia Maletzki1, Yvonne Rosche2, Christin Riess2
1Molecular Oncology and Immunotherapy, Department of General Surgery, 18057 Rostock, Germany.
Abstract:
Arginine auxotrophy constitutes the Achilles' heel for several tumors, among them glioblastoma multiforme (GBM). Hence, arginine-depleting enzymes such as arginine deiminase (ADI) from Streptococcus pyogenes are promising for treatment of primary and maybe even refractory GBM. Based on our previous study in which ADI-susceptibility was shown on a panel of patient-derived GBM cell lines, we here aimed at deciphering underlying molecular mechanisms of ADI-mediated growth inhibition. We found that ADI (35 mU/mL) initially induces a cellular stress-response that is characterized by upregulation of genes primarily belonging to the heat-shock protein family. In addition to autophagocytosis, we show for the first time that senescence constitutes another cellular response mechanism upon ADI-treatment and that this bacterial enzyme is able to act as radiosensitizer (¼ cases). Long-term treatment schedules revealed no resistance development, with treated cells showing morphological signs of cell stress. Next, several combination strategies were employed to optimize ADI-based treatment. Simultaneous and sequential S. pyogenes ADI-based combinations included substances acting at different molecular pathways (curcumin, resveratrol, quinacrine, and sorafenib, 2 × 72 h treatment). Adding drugs to GBM cell lines (n = 4, including a matched pair of primary and recurrent GBM in one case) accelerated and potentiated ADI-mediated cytotoxicity. Autophagy was identified as the main cause of tumor growth inhibition. Of note, residual cells again showed classical signs of senescence in most combinations. Our results suggest an alternative treatment regimen for this fatal cancer type which circumvents many of the traditional barriers. Using the metabolic defect in GBM thus warrants further (pre-) clinical evaluation.
Insights
Arginine deiminase (ADI) triggers stress responses, including senescence and autophagy, to inhibit glioblastoma multiforme (GBM) growth. Combining ADI with other drugs enhances its effectiveness, suggesting a novel treatment strategy for this fatal cancer.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Glioblastoma multiforme (GBM) is arginine auxotrophic, making it vulnerable to arginine depletion.
- Arginine deiminase (ADI) from Streptococcus pyogenes depletes arginine and shows promise for GBM treatment.
Purpose of the Study:
- To investigate the molecular mechanisms of ADI-mediated growth inhibition in GBM.
- To evaluate ADI as a radiosensitizer and explore combination therapies for GBM.
Main Methods:
- Treatment of patient-derived GBM cell lines with ADI (35 mU/mL).
- Analysis of gene expression, autophagy, and senescence.
- Combination studies with curcumin, resveratrol, quinacrine, and sorafenib.
- Assessment of ADI as a radiosensitizer.
Main Results:
- ADI induced cellular stress responses, including heat-shock protein upregulation, autophagy, and senescence.
- ADI demonstrated radiosensitizing potential in a subset of GBM cases.
- No resistance to long-term ADI treatment was observed.
- Combination therapies with ADI accelerated and potentiated cytotoxicity, with autophagy as the primary mechanism of inhibition.
- Residual cells in combination treatments exhibited senescence.
Conclusions:
- ADI treatment induces stress responses, autophagy, and senescence in GBM cells.
- ADI can act as a radiosensitizer and its combination with other drugs enhances anti-GBM effects.
- Targeting GBM's metabolic vulnerability with ADI-based strategies warrants further clinical investigation.
