Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-β/STAT3 Pathway

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options.
• Conventional chemotherapy, such as gemcitabine, shows poor efficacy and significant side effects for PDAC.
• Novel therapeutic strategies are crucial for improving treatment outcomes in PDAC.

Purpose of the Study:

• To evaluate the combined anticancer effects of melatonin and sorafenib against PDAC.
• To investigate the underlying mechanisms of this novel combination therapy.

Main Methods:

• In vitro and in vivo studies using apoptosis assays and PDAC xenograft models.
• Phospho-receptor tyrosine kinase (RTK) array and phospho-tyrosine kinase array analysis.
• Western blotting, proximity ligation assay, and immunoprecipitation for mechanistic validation.

Main Results:

• Melatonin and sorafenib demonstrated synergistic suppression of PDAC growth in vitro and in vivo.
• The combination therapy significantly increased PDAC cell apoptosis and induced mitochondrial dysfunction.
• The enhanced efficacy was attributed to the blockade of the PDGFR-β/STAT3 signaling pathway and MT-mediated STAT3.

Conclusions:

• Melatonin enhances sorafenib's anticancer activity in PDAC through PDGFR-β/STAT3 pathway downregulation.
• Melatonin receptor (MT)-mediated STAT3 signaling is involved in the synergistic effect.
• The combination of melatonin and sorafenib represents a potential therapeutic strategy for PDAC.