Dichloroacetic acid and rapamycin synergistically inhibit tumor progression

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mammalian target of rapamycin (mTOR) signaling is crucial for cellular anabolism and frequently hyperactive in cancer.
• Rapamycin, an FDA-approved mTOR complex 1 (mTORC1) inhibitor, shows efficacy in cancer treatment but primarily inhibits growth rather than inducing apoptosis.
• Pyruvate dehydrogenase complex (PDHc) regulates mitochondrial pyruvate oxidation; its inactivation is observed in cancer cells, offering protection against senescence and NAD+ depletion.

Purpose of the Study:

• To investigate the effect of rapamycin on PDHc activity in cancer cells.
• To elucidate the mechanism by which rapamycin influences PDHc.
• To determine if modulating PDHc activity can enhance cancer cell sensitivity to rapamycin.

Main Methods:

• Treatment of cancer cells with rapamycin.
• Assessment of PDHA1 phosphorylation and PDHc activity.
• In vitro and in vivo experiments using dichloroacetic acid (DCA) as a pyruvate dehydrogenase kinase (PDK) inhibitor.

Main Results:

• Rapamycin treatment induced PDHA1 phosphorylation, leading to mTOR-dependent PDHc inactivation.
• PDHc inactivation by rapamycin reduced cancer cell sensitivity to the drug.
• Combined treatment with DCA and rapamycin restored PDHc activity and increased cancer cell susceptibility to rapamycin in vitro and in vivo.

Conclusions:

• Rapamycin-induced PDHc inactivation represents a resistance mechanism to mTOR inhibition in cancer.
• Rebooting PDHc activity with DCA can overcome rapamycin resistance.
• Combination therapy targeting both mTOR and PDHc pathways holds promise for improving cancer treatment outcomes.