Metformin dual-targets metabolism and survival pathways in BPDCN

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy.
• Limited therapeutic options exist for BPDCN patients.
• Metformin, a common antidiabetic drug, exhibits anticancer properties, but its efficacy in BPDCN is unexplored.

Purpose of the Study:

• To investigate the effects of metformin on BPDCN cell viability, apoptosis, and underlying molecular mechanisms.
• To evaluate metformin's therapeutic potential in preclinical BPDCN models.

Main Methods:

• Treatment of established and primary BPDCN cell lines with metformin.
• Assessment of cell viability, apoptosis (caspase-dependent), and intrinsic apoptotic pathway activation.
• Analysis of metformin's impact on cellular metabolism (AMPK, mitochondrial respiration, glycolysis) and oncogenic signaling (Akt/mTOR, NF-κB, STAT3, STAT5).
• In vivo studies using mouse models to assess metformin's effects on tumor infiltration and signaling pathways.

Main Results:

• Metformin significantly reduced BPDCN cell viability and induced apoptosis via the intrinsic pathway.
• Metformin activated AMPK, disrupted mitochondrial respiration and glycolysis, and inhibited Akt/mTOR, NF-κB, STAT3, and STAT5 signaling.
• In vivo, metformin decreased spleen tumor infiltration and modulated NF-κB and STAT5 signaling, though overall disease progression impact was limited.

Conclusions:

• Metformin demonstrates multifaceted anticancer activity against BPDCN by targeting metabolic and survival pathways.
• Metformin shows promise as a potential therapeutic agent for blastic plasmacytoid dendritic cell neoplasm.
• Further research is warranted to explore metformin's clinical utility in BPDCN treatment.