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Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-κB
Huai-Qiang Ju1,2, Hao Li1,2, Tian Tian1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Abstract:
Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.
Insights
Melatonin suppresses pancreatic cancer by inhibiting nuclear factor-κB (NF-κB) signaling. This approach enhances gemcitabine effectiveness, offering a potential new treatment strategy for pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor-κB (NF-κB) pathway activation drives pancreatic ductal adenocarcinoma (PDAC) aggressiveness and gemcitabine resistance.
- Targeting the NF-κB pathway presents a significant challenge in PDAC therapy.
Purpose of the Study:
- To investigate melatonin's potential to inhibit NF-κB signaling and overcome gemcitabine resistance in pancreatic cancer.
- To evaluate melatonin's effects on PDAC cell proliferation, invasion, and chemosensitivity.
Main Methods:
- In vitro studies using PDAC cell lines (MiaPaCa-2, AsPc-1, Panc-28) and gemcitabine-resistant cells (MiaPaCa-2/GR).
- Assessment of NF-κB activity, IκBα phosphorylation, and gene expression.
- In vivo evaluation using an orthotopic xenograft mouse model treated with melatonin and/or gemcitabine.
Main Results:
- Melatonin inhibited NF-κB activity by suppressing IκBα phosphorylation and downregulating NF-κB target genes.
- Melatonin reduced PDAC cell proliferation and invasion independently of its receptor.
- Melatonin enhanced gemcitabine-induced cytotoxicity in PDAC cells.
- Combination therapy (melatonin + gemcitabine) resulted in greater tumor burden reduction in vivo compared to single agents.
Conclusions:
- Melatonin inhibits PDAC cell proliferation and invasion and overcomes gemcitabine resistance via NF-κB pathway inhibition.
- Melatonin demonstrates preclinical efficacy as a therapeutic agent for PDAC, alone or in combination with gemcitabine.
- Further clinical investigation of melatonin for PDAC treatment is warranted.
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