Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and
Haibo Yan1, Dongsheng Li2, Min Yang1
1School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, P. R. China.
Abstract:
Simultaneous targeting of glycolysis and oxidative phosphorylation (OXPHOS) is an effective strategy for overcoming the metabolic plasticity of pancreatic ductal adenocarcinoma (PDAC). In this study, we present compound 14c, a rationally designed, mitochondria-targeted small molecule that disrupts PDAC energy metabolism. Compound 14c markedly inhibited PDAC cell glycolysis and mitochondrial function, as evidenced by the PDKs inhibition and the downregulation of OXPHOS-associated proteins, including SDHB and SIRT3, in vitro and in vivo. Mechanistically, 14c induced ferroptotic cell death, accompanied by lipid peroxidation, redox imbalance, and mitochondrial dysfunction. Importantly, 14c also elicited hallmarks of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release. In a syngeneic PANC02 model, 14c suppressed tumor growth with minimal systemic toxicity and recapitulated the metabolic inhibition and ICD-associated phenotypes observed in vitro. These findings support that 14c could be used as a dual metabolic inhibitor and ICD inducer in PDAC therapy.
Insights
A novel mitochondria-targeted compound, 14c, effectively inhibits pancreatic cancer cell metabolism and induces cell death. This dual-action molecule shows promise as a pancreatic ductal adenocarcinoma (PDAC) therapy by disrupting energy production and triggering an immune response.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits significant metabolic plasticity, necessitating dual-targeting strategies.
- Simultaneous inhibition of glycolysis and oxidative phosphorylation (OXPHOS) presents a viable therapeutic approach for PDAC.
- Mitochondria-targeted small molecules offer a promising avenue for disrupting cancer cell metabolism.
Purpose of the Study:
- To develop and characterize a novel mitochondria-targeted small molecule, compound 14c, for disrupting PDAC energy metabolism.
- To investigate the mechanistic effects of compound 14c on PDAC cell glycolysis, mitochondrial function, and cell death pathways.
- To evaluate the in vivo efficacy and safety of compound 14c in a syngeneic PDAC mouse model.
Main Methods:
- In vitro assays assessing glycolysis and mitochondrial function, including PDKs inhibition and OXPHOS protein analysis (SDHB, SIRT3).
- Analysis of ferroptosis induction markers (lipid peroxidation, redox imbalance) and mitochondrial dysfunction.
- Assessment of immunogenic cell death (ICD) hallmarks (calreticulin exposure, HMGB1 release).
- In vivo studies using a syngeneic PANC02 PDAC model to evaluate tumor growth suppression and systemic toxicity.
Main Results:
- Compound 14c significantly inhibited PDAC cell glycolysis and mitochondrial function, confirmed by PDKs inhibition and reduced OXPHOS protein levels.
- 14c treatment induced ferroptotic cell death, characterized by increased lipid peroxidation, redox imbalance, and mitochondrial dysfunction.
- The compound elicited hallmarks of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release.
- In vivo, 14c suppressed tumor growth in the PANC02 model with minimal systemic toxicity, mirroring in vitro metabolic and ICD effects.
Conclusions:
- Compound 14c acts as a potent dual inhibitor of glycolysis and OXPHOS in PDAC.
- 14c effectively induces both ferroptosis and immunogenic cell death in pancreatic cancer cells.
- The findings support the potential of compound 14c as a novel therapeutic agent for pancreatic ductal adenocarcinoma, combining metabolic disruption with immune activation.
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