Synergistic therapeutic impact of dichloroacetate nanoparticles and doxorubicin in modulating pyruvate dehydrogenase kinase in breast carcinoma model

TL;DR

This study explores combining dichloroacetate nanoparticles and doxorubicin to target cancer metabolism and reduce tumor growth in breast cancer.

Contribution

The novel use of dichloroacetate nanoparticles in combination with doxorubicin to modulate PDK enzymes in breast carcinoma is presented.

Findings

Dox/DCA-PNPs treatment reduced tumor profile and organ damage while suppressing PDK genes.

Dox/DCA-PNPs induced apoptosis and cell cycle arrest in cancer cells.

Dox showed stronger binding affinity to PDK enzymes compared to DCA.

Abstract

Breast cancer is treated with chemotherapies causing severe organ side effects. Increased pyruvate dehydrogenase kinase (PDK) enzymes in cancer cell metabolism lead to tumor resistance. This study examined dichloroacetate nanoparticles (DCA-PNPs)/doxorubicin (Dox) impact on PDK enzymes in Ehrlich ascites carcinoma (EAC) cells. DCA-PNPs were synthesized using poly D, L-lactic-co-glycolide, polyvinyl alcohol, and characterized by encapsulation efficiency, drug-loading capacity, spectroscopy, and microscopy. Molecular docking and ADMET analysis were conducted. Seventy female CD1 mice were divided into 10 groups (n = 7). (Gp1) was normal negative control. Gp2 to Gp4 received DCA (50 mg/kg), DCA-PNPs (50 mg/kg), and Dox (0.2 mg/kg), intraperitoneal (i.p.) injection. Gp5 to Gp10 were inoculated with EAC cells 0.5 × 106 /mouse. GP5 were untreated group, served as a positive control (EAC-untreated mice or EAC-bearing mice group). GP6 to GP10 were treated with Dox, DCA, DCA-PNPs, Dox/DCA, and Dox/DCA-PNPs (i.p.). On day 14, tumor profile, molecular analysis, and hepatorenal alterations were assessed. Results showed DCA-PNPs size was 22.5 ± 1.72 nm, and (ζ) was − 9.5 mV. Dox exhibited strongest binding affinity across PDKs (− 7.7 to − 8.3 kcal/mol), while DCA showed modest affinities (− 3.7 to − 4.0 kcal/mol). Dox/DCA-PNPs treatment decreased tumor profile and hepatorenal alterations with PDKs gene suppression, increased cancer cell apoptosis and cycle arrest at G0/G1 phase (76.1 and 64.8%). Dox/DCA-PNPs demonstrated anti-tumor activity via inhibiting PDK enzyme.

The online version contains supplementary material available at 10.1038/s41598-025-34562-7.

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